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Harrison RK, Allen K, Naatz A, Corbett J, McIntosh J, Cruz M. Fetal macrosomia and placental expression of fibroblast growth factor 21 and peroxisome proliferator-activated receptor alpha. Syst Biol Reprod Med 2025; 71:196-205. [PMID: 40411500 DOI: 10.1080/19396368.2025.2504450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/26/2025]
Abstract
Macrosomia (birth weight >4000 g) is a product of endocrine dysfunction in utero leading to fetal overgrowth and can lead to maternal and infant morbidity. Fibroblast growth factor 21 (FGF21) and its transcription factor, peroxisome proliferator-activated receptor alpha (PPARα), are found in the placenta and are associated with abnormal metabolic states. Their relationship to the placental dysregulation that leads to macrosomia is unknown. We sought to evaluate the relationship between protein expression of FGF21 and PPARα in placental samples from infants with macrosomia compared to controls (<4000 g) on both the maternal and fetal sides of the placenta. Placental specimens were collected at the time of delivery and protein levels of FGF21 and PPARα were quantified via Western Blot analysis and normalized to GAPDH. Student's t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Chi-squared analysis, and Spearman's correlation were used for statistical analyses. Baseline characteristics were similar across both groups. FGF21 and PPARα levels on the maternal side of the placenta did not differ based on presence of macrosomia. PPARα expression was statistically significantly lower on the fetal side in infants with macrosomia. In controls alone, FGF21 and PPARα trended lower on the maternal side compared to the fetal side although this was not statistically significant. PPARα and FGF21 were positively correlated throughout the placenta. We found that lower PPARα expression on the fetal side of placenta was noted in infants with macrosomia, identifying a possible contribution to the growth discrepancy in this group. PPARα and FGF21 are strongly correlated in the human placenta.
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Affiliation(s)
- Rachel K Harrison
- Deparment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Advocate Aurora Health, Oak Lawn, IL, USA (present)
| | - Katherine Allen
- Medical College of Wisconsin, Milwaukee, WI, USA
- Mercy Health Deparment of Obstetrics and Gynecology, Muskegon, MI, USA (present)
| | - Aaron Naatz
- Deparment of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John Corbett
- Deparment of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jennifer McIntosh
- Deparment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Meredith Cruz
- Deparment of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
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2
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Cetti F, Ossoli A, Garavaglia C, Da Dalt L, Norata GD, Gomaraschi M. PPAR-mediated reduction of lipid accumulation in hepatocytes involves the autophagy-lysosome-mitochondrion axis. Ann Med 2025; 57:2497112. [PMID: 40289698 PMCID: PMC12039397 DOI: 10.1080/07853890.2025.2497112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 03/25/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND AND AIM Lipid accumulation in hepatocytes is reduced by the activation of the peroxisome proliferator-activated receptor (PPAR) α, which is associated with increased lysosomal acid lipase (LAL) activity, transcription factor EB (TFEB) expression, and mitochondrial β-oxidation.Aim of the study was to assess whether the three isoforms of PPAR, i.e. α, δ and γ, share the same ability to reduce lipid accumulation in hepatocytes and to clarify the involvement of autophagy activation, lysosomal hydrolysis, and mitochondrial β-oxidation in lipid clearance induced by PPARs. METHODS HepG2 cells were treated with oleate/palmitate (O/P) to induce lipid accumulation and exposed to the PPARα agonist fenofibric acid, the γ agonist pioglitazone, the δ agonist seladelpar, or the dual α/γ agonist saroglitazar. RESULTS The treatment of HepG2 cells with fenofibric acid, pioglitazone, seladelpar, or saroglitazar halved lipid accumulation induced by O/P. PPAR agonists increased TFEB, p62, and LC3 expression and rescued LAL impairment induced by O/P. Moreover, PPAR agonists significantly increased mitochondrial mass and the expression of genes involved in mitochondrial dynamics and fatty acid catabolism. Interestingly, PPAR agonists lost their ability to reduce lipid accumulation when autophagic flux, LAL activity, or fatty acid transport in the mitochondria were blocked by specific inhibitors. CONCLUSION All PPAR agonists were able to promote the clearance of lipids in cells loaded with long-chain fatty acids. The key role of acid hydrolysis to generate fatty acids, which can be then catabolized in the mitochondria, and the ability of the PPAR system to sustain each phase of this clearing process were elucidated.
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Affiliation(s)
- Federica Cetti
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Alice Ossoli
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Carola Garavaglia
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Lorenzo Da Dalt
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Monica Gomaraschi
- Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
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3
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Choi MA, Rose S, Langouët S. Per- and polyfluoroalkyl substances as potentiators of hepatotoxicity in an exposome framework: Current challenges of environmental toxicology. Toxicology 2025; 515:154167. [PMID: 40300710 DOI: 10.1016/j.tox.2025.154167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/17/2025] [Accepted: 04/26/2025] [Indexed: 05/01/2025]
Abstract
Chronic liver diseases, including metabolic dysfunction-associated steatosic liver disease (MASLD) and hepatocellular carcinoma (HCC), are on the rise, potentially due to daily exposure to complex mixtures of chemical compounds forming part of the exposome. Understanding the mechanisms involved in hepatotoxicity of these mixtures is essential to identify common molecular targets that may highlight potential interactions at the molecular level. We illustrated this issue with two families of environmental contaminants, per- and polyfluoroalkyl substances (PFAS) and heterocyclic aromatic amines (HAAs), both of which could be involved in the progression of chronic liver diseases, and whose toxicity may be potentiated by interactions at the level of xenobiotic metabolism. In the study of exposome effects on chronic liver disease, New Approach Methodologies (NAMs) including omics analyses and data from various in vitro, in vivo and in silico approaches, are crucial for improving predictivity of toxicological studies in humans while reducing animal experimentation. Additionally, the development of complex in vitro human liver cell models, such as organoids, is essential to avoid interspecies differences that minimize the risk for humans. All together, these approaches will contribute to construct Adverse Outcome Pathways (AOPs) and could be applied not only to PFAS mixtures but also to other chemical families, providing valuable insights into mixture hepatotoxicity prediction in the study of the exposome. A better understanding of toxicological mechanisms will clarify the role of environmental contaminant mixtures in the development of MASLD and HCC, supporting risk assessment for better treatment, monitoring and prevention strategies.
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Affiliation(s)
- Minna A Choi
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Rose
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Langouët
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France.
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4
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Chen Y, Liao Z, Mao J, Wang W, Liu Y, Dai W, Wen Z, Liu S, Chen Y, Ma Y, Wang X, Li Z. Discovery of the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis. Eur J Med Chem 2025; 291:117635. [PMID: 40279770 DOI: 10.1016/j.ejmech.2025.117635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/09/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound 27 was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC50 = 0.65 μM, FABP4 IC50 = 1.08 μM, PPARα EC50 = 9.19 μM, PPARγ EC50 = 2.20 μM, PPARδ EC50 = 1.58 μM). Further MST assay confirmed the direct interaction of compound 27 and FABP1, providing a robust validation of its target specificity. In MASH mice, compound 27 exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.
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Affiliation(s)
- Ya Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zibin Liao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Jianming Mao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Wenxin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yuxia Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Wei Dai
- Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China
| | - Zheng Wen
- Department of Emergency, Baiyun Hospital of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, PR China
| | - Sishi Liu
- Department of Gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Yayi Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Yiming Ma
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xiaoying Wang
- Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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5
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Katsouda A, Markou M, Valakos D, Theodorou I, Papapetropoulos A. Cth/Mpst double ablation results in early onset fatty liver disease in lean mice. Redox Biol 2025; 83:103641. [PMID: 40253747 PMCID: PMC12023873 DOI: 10.1016/j.redox.2025.103641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/14/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), a condition that stems from hepatic lipid accumulation in the absence of liver damage and overt inflammation, has become the most common hepatic disorder worldwide. Hydrogen sulfide (H2S), a gasotrasmitter, endogenously generated mainly by cystathionine-γ lyase (CTH), cystathionine-β synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes, exhibits protective effect in steatosis. Herein, we have demonstrated that CTH and MPST play a central role in MAFLD pathogenesis. Young Cth/Mpst knockout (Cth/Mpst-/-) mice, fed a normal diet, had increased liver mass caused by enhanced hepatic lipid accumulation. Decreased insulin and glucose sensitivity was observed in CTH/MPST-deficient mice. At the cellular level, CTH/MPST inhibition resulted in increased lipid deposition and glucose uptake in hepatocytes. Transcriptome analysis revealed significant upregulation of cholesterol biosynthesis and SREBP-related genes in the liver of Cth/Mpst-/- mice. Transcription factor enrichment analysis of differentially expressed genes between two genotypes, revealed a major impact of LXR, RXR and PPARA in the observed phenotype. Sulfide donor (SG1002) treatment attenuated the fatty liver disease of CTH/MPST-deficient mice. Our findings underline the importance of endogenously produced H2S in the pathogenesis of MAFLD and introduce the Cth/Mpst-/- mouse as a new animal model of early onset hepatic steatosis.
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Affiliation(s)
- Antonia Katsouda
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Maria Markou
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Valakos
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioannis Theodorou
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Papapetropoulos
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
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Tu C, Qian C, Li S, Lin DY, Liu ZY, Ouyang WG, Kang XL, Chen F, Song S, Cai SQ. Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis. NATURE AGING 2025:10.1038/s43587-025-00862-w. [PMID: 40389730 DOI: 10.1038/s43587-025-00862-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 04/01/2025] [Indexed: 05/21/2025]
Abstract
With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.
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Affiliation(s)
- Chuantao Tu
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
| | - Cheng Qian
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| | - Shuyu Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - De-Ying Lin
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhi-Yang Liu
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| | - Wan-Gan Ouyang
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xin-Lei Kang
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| | - Fangyuan Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shu Song
- Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Shi-Qing Cai
- Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
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7
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Zhao Y, Wang Y, Chen L, Chen H, Tang Y, He Y, Yao P. Accelerated Biological Aging, Genetic Susceptibility, and Non-Alcoholic Fatty Liver Disease: Two Prospective Cohort Studies. Nutrients 2025; 17:1618. [PMID: 40431359 DOI: 10.3390/nu17101618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Biological aging is considered a vital risk factor for age-related diseases, but its role in non-alcoholic fatty liver disease (NAFLD) remains uncertain. This study aimed to evaluate the associations of biological aging with NAFLD and the modified effect of genetic susceptibility. Methods: This study included 329,040 participants from the UK Biobank and 6783 participants from the Dongfeng-Tongji Cohort in China. We calculated the chronological age-adjusted biological age as a surrogate measure for biological aging. Accelerated aging was defined as biological age that exceeded chronological age. The association between biological aging and the risk of NAFLD was assessed in the two cohorts. Polygenic risk scores (PRSs) were used to determine genetic susceptibility for NAFLD in the UK Biobank and further analyze the interaction with biological aging. Results: In the UK Biobank, one year older in age-adjusted biological age increased prevalent NAFLD risk by 6%. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of NAFLD by accelerated aging were 1.35 (1.17, 1.56) and 1.69 (1.54, 1.85) compared to non-aging. In the Dongfeng-Tongji Cohort, biological aging was prospectively associated with NAFLD (accelerated aging: odds ratio (OR) (95% CI) = 1.18 (1.03, 1.36)). In the UK Biobank, high genetic risk was significantly associated with higher NAFLD risk compared to low genetic risk (HRs (95% CIs) = 1.65 (1.40, 1.95)). Analyses of joint effects showed that participants with high PRS and accelerated aging had the highest risk of NAFLD [2.66 (2.98, 3.57) and 2.06 (2.36, 3.96)]. However, biological aging was prospectively associated with NAFLD among participants regardless of genetic risk. There was no significant interaction between genetic risk and biological aging. Conclusions: Accelerated biological aging was associated with a higher risk of NAFLD independent of genetic susceptibility. Identifying populations with accelerated biological aging by the use of surrogate measures and timely intervention may be beneficial for the prevention of NAFLD.
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Affiliation(s)
- Ying Zhao
- School of Public Health, Kunming Medical University, Kunming 650500, China
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Chen
- Hubei Key Laboratory of Lipid Chemistry and Nutrition, and Key Laboratory of Oilseeds Processing, Ministry of Agriculture, Oil Crops and Lipids Process Technology National & Local Joint Engineering Laboratory, Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences, Wuhan 430062, China
| | - Huimin Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuhan Tang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuefeng He
- School of Public Health, Kunming Medical University, Kunming 650500, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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8
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Ma F, Longo M, Meroni M, Bhattacharya D, Paolini E, Mughal S, Hussain S, Anand SK, Gupta N, Zhu Y, Navarro-Corcuera A, Li K, Prakash S, Cogliati B, Wang S, Huang X, Wang X, Yurdagul A, Rom O, Wang L, Fried SK, Dongiovanni P, Friedman SL, Cai B. EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis. Cell Metab 2025; 37:1152-1170.e7. [PMID: 40015280 PMCID: PMC12058419 DOI: 10.1016/j.cmet.2025.01.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/27/2024] [Accepted: 01/22/2025] [Indexed: 03/01/2025]
Abstract
Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.
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Affiliation(s)
- Fanglin Ma
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Miriam Longo
- Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Marica Meroni
- Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Dipankar Bhattacharya
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Erika Paolini
- Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Shama Mughal
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Syed Hussain
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sumit Kumar Anand
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Neha Gupta
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yiwei Zhu
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Navarro-Corcuera
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kenneth Li
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Satya Prakash
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bruno Cogliati
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Shuang Wang
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Xin Huang
- Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Arif Yurdagul
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Liheng Wang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Susan K Fried
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Paola Dongiovanni
- Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bishuang Cai
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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9
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Meng Y, Zhang J, Liu Y, Zhu Y, Lv H, Xia F, Guo Q, Shi Q, Qiu C, Wang J. The biomedical application of inorganic metal nanoparticles in aging and aging-associated diseases. J Adv Res 2025; 71:551-570. [PMID: 38821357 DOI: 10.1016/j.jare.2024.05.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 06/02/2024] Open
Abstract
Aging and aging-associated diseases (AAD), including neurodegenerative disease, cancer, cardiovascular diseases, and diabetes, are inevitable process. With the gradual improvement of life style, life expectancy is gradually extended. However, the extended lifespan has not reduced the incidence of disease, and most elderly people are in ill-health state in their later years. Hence, understanding aging and AAD are significant for reducing the burden of the elderly. Inorganic metal nanoparticles (IMNPs) predominantly include gold, silver, iron, zinc, titanium, thallium, platinum, cerium, copper NPs, which has been widely used to prevent and treat aging and AAD due to their superior properties (essential metal ions for human body, easily synthesis and modification, magnetism). Therefore, a systematic review of common morphological alternations of senescent cells, altered genes and signal pathways in aging and AAD, and biomedical applications of IMNPs in aging and AAD is crucial for the further research and development of IMNPs in aging and AAD. This review focus on the existing research on cellular senescence, aging and AAD, as well as the applications of IMNPs in aging and AAD in the past decade. This review aims to provide cutting-edge knowledge involved with aging and AAD, the application of IMNPs in aging and AAD to promote the biomedical application of IMNPs in aging and AAD.
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Affiliation(s)
- Yuqing Meng
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junzhe Zhang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yanqing Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yongping Zhu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Haining Lv
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fei Xia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qiuyan Guo
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qianli Shi
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Chong Qiu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Jigang Wang
- Department of Urology, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, China; State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, China.
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10
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He L, Zhang L, Meng F, Wei J, Chen F, Qin S, Jin G, Cao H. Dietary emulsifier Polysorbate 80-induced lipotoxicity promotes intestinal senescence. Food Res Int 2025; 209:116165. [PMID: 40253120 DOI: 10.1016/j.foodres.2025.116165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/11/2025] [Accepted: 03/09/2025] [Indexed: 04/21/2025]
Abstract
Intestinal senescence, often characterized by increased oxidative stress, is linked to gastrointestinal disorders such as inflammatory bowel disease and colorectal cancer. While previous studies have suggested that diets rich in food additives, such as the emulsifier Polysorbate 80 (P80), may influence gut health, the impact of P80 exposure on intestinal senescence remains unclear. This study aimed to explore the effects of P80 on intestinal senescence in a senescence-accelerated mouse prone model. The results revealed that P80 exposure could damage the intestinal barrier, induce oxidative stress, and accelerate intestinal senescence. Mechanistically, P80 activated the peroxisome proliferator-activated receptor-α (PPARα) and fatty acid-binding protein 1 (FABP1) axis, increasing intestinal fatty acid absorption and triggering lipotoxicity, which promoted senescence. Additionally, P80 exacerbated D-galactose-induced epithelial cell senescence and lipid accumulation via the PPARα signalling pathway. Importantly, the PPARα antagonist GW6471 mitigated fatty acid uptake and reduced senescence in the intestine. In conclusion, the emulsifier P80 accelerated intestinal senescence by regulating the PPARα-FABP1 axis to induce intestinal fatty acid uptake and lipotoxicity, suggesting new insights into the adverse effects of food additives on gut health.
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Affiliation(s)
- Linlin He
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Lan Zhang
- Department of Infective disease, Tianjin First Central Hospital, Tianjin, China
| | - Fanyi Meng
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Fei Chen
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Siqi Qin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Ge Jin
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China..
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China..
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11
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Nielsen G, Gondim DD, Cave MC, Heiger-Bernays WJ, Webster TF, Schlezinger JJ. Perfluorooctanoic acid increases serum cholesterol in a PPARα-dependent manner in female mice. Arch Toxicol 2025; 99:2087-2105. [PMID: 40021516 DOI: 10.1007/s00204-025-03984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 02/05/2025] [Indexed: 03/03/2025]
Abstract
Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent chemicals that are pervasive in the environment leading to widespread exposure for humans. Perfluorooctanoic acid (PFOA), one of the most commonly measured PFAS in people, disrupts liver and serum lipid homeostasis as shown in animal toxicity and human epidemiological studies. We tested the hypothesis that the effects of PFOA exposure in mice expressing mouse PPARα (mPPARα) are driven largely through PPARα-dependent mechanisms while non-PPARα dependent mechanisms will be more apparent in mice expressing human PPARα (hPPARα). Female and male mPPARα, hPPARα, and PPARα null mice were exposed to PFOA (0.5, 1.4 or 6.2 mg PFOA/L) via drinking water for 14 weeks. Concurrently, mice consumed an American diet containing human diet-relevant amounts of fat and cholesterol. Here, we focused on the effects in female mice, given the dearth of data reported on PFAS-induced effects in females. Increasing the duration of PFOA exposure reduced weight gain in all genotypes of female mice while end-of-study body fat was lower in PFOA exposed hPPARα and PPARα null mice. Serum cholesterol, but not triacylglyceride, concentrations were increased by PFOA exposure in a PPARα-dependent manner. Hepatic triacylglycerides were higher in vehicle-exposed mPPARα and PPARα null mice than hPPARα mice, and PFOA significantly reduced concentrations in mPPARα and PPARα null mice only. In contrast, PFOA increased hepatic cholesterol content in a PPARα-dependent manner. Changes in liver and serum cholesterol may be explained by a strong, PPARα-dependent downregulation of Cyp7a1 expression. PFOA significantly increased PPARα target gene expression in mPPARα mice. Other nuclear receptors were examined: CAR target gene expression was only induced by PFOA in hPPARα and PPARα null mice. PXR target gene expression was induced by PFOA in all genotypes. Results were similar in male mice with two exceptions: (1) vehicle-exposed male mice of all genotypes were equally susceptible to diet-induced hepatic steatosis; (2) male mice drank less water, resulting in lower serum PFOA levels, which may explain the less significant changes in lipid endpoints. Overall, our results show that PFOA modifies triacylglyceride and cholesterol homeostasis independently and that PPARα plays an important role in PFOA-induced increases in liver and serum cholesterol.
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Affiliation(s)
- G Nielsen
- Department of Environmental Health, School of Public Heath, Boston University, Boston, MA, USA
| | - D D Gondim
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY, USA
| | - M C Cave
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY, USA
| | - W J Heiger-Bernays
- Department of Environmental Health, School of Public Heath, Boston University, Boston, MA, USA
| | - T F Webster
- Department of Environmental Health, School of Public Heath, Boston University, Boston, MA, USA
| | - J J Schlezinger
- Department of Environmental Health, School of Public Heath, Boston University, Boston, MA, USA.
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12
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Hu S, Ai Y, Hu C, Cassim Bawa FN, Xu Y. Transcription factors, metabolic dysfunction-associated fatty liver disease, and therapeutic implications. Genes Dis 2025; 12:101372. [PMID: 39911797 PMCID: PMC11795806 DOI: 10.1016/j.gendis.2024.101372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 03/27/2024] [Accepted: 06/21/2024] [Indexed: 02/07/2025] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a spectrum of liver diseases ranging from metabolic dysfunction-associated fatty liver to metabolic dysfunction-associated steatohepatitis, which may progress to liver cirrhosis and hepatocellular carcinoma. Several mechanisms, including obesity, insulin resistance, dyslipidemia, inflammation, apoptosis, mitochondrial dysfunction, and reactive oxygen species, have been proposed to underlie the progression of MAFLD. Transcription factors are proteins that specifically bind to DNA sequences to regulate the transcription of target genes. Numerous transcription factors regulate MAFLD by modulating the transcription of genes involved in steatosis, inflammation, apoptosis, and fibrosis. Here, we review the pathological factors associated with MAFLD, with a particular emphasis on the transcription factors that contribute to the progression of MAFLD and their therapeutic implications.
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Affiliation(s)
- Shuwei Hu
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Yingjie Ai
- Department of Pathology of School of Basic Medical Sciences, Department of Gastroenterology and Hepatology of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chencheng Hu
- Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Fathima N. Cassim Bawa
- Institute of Diabetes, Obesity and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yanyong Xu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Frontier Innovation Center, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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13
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Uchiyama LF, Nguyen A, Qian K, Cui L, Pham KT, Xiao X, Gao Y, Shimanaka Y, Tol MJ, Vergnes L, Reue K, Tontonoz P. PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes. Proc Natl Acad Sci U S A 2025; 122:e2426338122. [PMID: 40258152 PMCID: PMC12054784 DOI: 10.1073/pnas.2426338122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/11/2025] [Indexed: 04/23/2025] Open
Abstract
Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.
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Affiliation(s)
- Lauren F. Uchiyama
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
- Molecular Biology Institute, University of California, Los Angeles, CA90095
| | - Alexander Nguyen
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA90095
| | - Kevin Qian
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
- Molecular Biology Institute, University of California, Los Angeles, CA90095
| | - Liujuan Cui
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
| | - Khoi T. Pham
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
| | - Xu Xiao
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
| | - Yajing Gao
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
| | - Yuta Shimanaka
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
| | - Marcus J. Tol
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
| | - Laurent Vergnes
- Department of Human Genetics, University of California, Los Angeles, CA90095
| | - Karen Reue
- Department of Human Genetics, University of California, Los Angeles, CA90095
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA90095
- Department of Biological Chemistry, University of California, Los Angeles, CA90095
- Molecular Biology Institute, University of California, Los Angeles, CA90095
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14
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Ding L, Chen JS, Xing YF, Li DM, Fu AQ, Tong X, Chen GC, Xu JY, Qin LQ. Effects of lactoferrin on high-fat and high-cholesterol diet-induced non-alcoholic fatty liver disease in mice. J Nutr Biochem 2025; 143:109938. [PMID: 40294723 DOI: 10.1016/j.jnutbio.2025.109938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 04/10/2025] [Accepted: 04/23/2025] [Indexed: 04/30/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, representing a growing public health burden. While previous studies indicated that lactoferrin (LF) alleviates hepatic lipid accumulation, a hallmark of NAFLD, the mechanisms involved are still elusive. Male C57BL/6 J mice were randomly divided into the control (CON), high-fat, high-cholesterol diet containing cholate (HFCCD), and HFCCD+LF groups and treated for 8 weeks' intervention. Liver and small intestine tissues were analyzed to investigate lipid metabolism and underlying mechanisms. Additionally, gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed. HFCCD feeding induced hepatic steatosis, while LF intervention improved lipid metabolism by reducing fatty acid synthesis and increasing lipolysis in the liver. Mechanistically, LF downregulated the protein expression of serotonin receptor 2A (HTR2A), which is related to lipogenesis, and upregulated the protein expression of peroxisome proliferator-activated receptor α (PPARα), which is one of the pivotal lipolytic genes, and its downstream effector, carnitine palmitoyl transferase-1A (CPT-1A), in the liver. Additionally, LF increased the relative abundance of gut microbiota related to glycolipid metabolism, such as Adlercreutzia, and decreased the relative abundance of 5-HT-promoting gut microbiota, such as Clostridia. Furthermore, LF increased the levels of SCFAs, which positively correlated with the relative abundance of Adlercreutzia. Our study suggests that LF intervention alleviates HFCCD-induced NAFLD in mice, which is potentially associated with regulation of the HTR2A-PPARa-CPT-1A pathway and gut microbiota composition.
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Affiliation(s)
- Li Ding
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Jin-Si Chen
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yi-Fei Xing
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - De-Ming Li
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute, Soochow University, Suzhou, Jiangsu, China
| | - An-Qi Fu
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Xing Tong
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Guo-Chong Chen
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
| | - Li-Qiang Qin
- School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
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15
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Hamblin MH, Boese AC, Murad R, Lee JP. PPARα Genetic Deletion Reveals Global Transcriptional Changes in the Brain and Exacerbates Cerebral Infarction in a Mouse Model of Stroke. Int J Mol Sci 2025; 26:4082. [PMID: 40362325 PMCID: PMC12071640 DOI: 10.3390/ijms26094082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is an unmet clinical need for pharmacological treatments that can improve ischemic stroke outcomes. In this study, we investigated the role of brain peroxisome proliferator-activated receptor alpha (PPARα) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPARα transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPARα knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPARα in brain ischemia. Our RNA-seq analysis showed that PPARα KO altered the expression of genes in mouse brains with known roles in ischemic stroke pathophysiology. We also identified many other differentially expressed genes (DEGs) upon the loss of PPARα that correlated with increased infarct size in our stroke model. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis revealed the upregulation of gene signatures for the positive regulation of leukocyte proliferation, apoptotic processes, acute-phase response, and cellular component disassembly in mouse stroke brains with PPARα KO. In addition, pathway analysis of our RNA-seq data revealed that TNFα signaling, IL6/STAT3 signaling, and epithelial-mesenchymal transition (EMT) gene signatures were increased in PPARα KO stroke brains. Our study highlights PPARα as an attractive drug target for ischemic stroke due to its transcriptional regulation of inflammation-, apoptosis-, and EMT-related genes in brain tissue following ischemia.
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Affiliation(s)
- Milton H. Hamblin
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA
- Health Sciences Center, Tulane University, New Orleans, LA 70112, USA
| | - Austin C. Boese
- School of Medicine, Emory University, Atlanta, GA 30322, USA;
| | - Rabi Murad
- Bioinformatics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;
| | - Jean-Pyo Lee
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
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16
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Lv W, Wang X, Feng Z, Sun C, Wu H, Zeng M, Gao T, Cao K, Xu J, Zou X, Yang T, Li H, Chen L, Liu J, Dong S, Feng Z. Allantoin Serves as a Novel Risk Factor for the Progression of MASLD. Antioxidants (Basel) 2025; 14:500. [PMID: 40427382 DOI: 10.3390/antiox14050500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/14/2025] [Accepted: 04/18/2025] [Indexed: 05/29/2025] Open
Abstract
Uric acid (UA), traditionally recognized as an extracellular antioxidant, exhibits paradoxical associations with metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanistic contributions remain elusive. Here, we integrate multi-modal evidence to explore the role of UA and its oxidative metabolite, allantoin, in MASLD progression. Analysis of UK Biobank data revealed a strong association between elevated UA levels and increased risks of MASLD and type 2 diabetes (T2D). However, Mendelian randomization analysis of over 2 million samples demonstrated causal effects of urate solely on serum triglycerides and T2D risk. Targeted metabolomics in an elderly Chinese cohort identified allantoin, an oxidative by-product of UA, significantly elevated in individuals with dyslipidemia or T2D, with serum allantoin levels positively correlated with fasting glucose, triglycerides, and cholesterol. Animal studies indicated that allantoin exacerbates hepatic lipid accumulation and glucose intolerance in high-fat diet mice, driven by increased hepatic lipid biogenesis and reduced bile acid production. Notably, further research revealed a strong binding affinity of allantoin for PPARα, leading to the suppression of PPARα activity, which promotes the progression of MASLD. These findings underscore the critical role of allantoin, rather than UA, as a critical driver of MASLD development, offering valuable insights for the prediction and management of hepatic metabolic disorders.
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Affiliation(s)
- Weiqiang Lv
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Xueqiang Wang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266100, China
| | - Zhaode Feng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Cunxiao Sun
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Hansen Wu
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Mengqi Zeng
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266100, China
| | - Tianlin Gao
- School of Public Health, Qingdao University, Qingdao 266071, China
| | - Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Jie Xu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Xuan Zou
- Department of Geriatrics Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Precision Medical Institute, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Tielin Yang
- Biomedical Informatics & Genomics Center, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Hao Li
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Lei Chen
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266100, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266100, China
| | - Shanshan Dong
- Biomedical Informatics & Genomics Center, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Zhihui Feng
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266100, China
- Interdisciplinary Research Center of Frontier Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
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17
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Uchiyama LF, Ordonez GPM, Pham KT, Kennelly JP, López Rodríguez M, Tran L, Tontonoz P, Nguyen A. PPARɑ variant V227A reduces plasma triglycerides through enhanced lipoprotein lipolysis. J Lipid Res 2025; 66:100806. [PMID: 40245984 DOI: 10.1016/j.jlr.2025.100806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 04/19/2025] Open
Abstract
Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes, yet their specific effects on metabolic gene expression are not well defined. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. Substitution with this variant in mice reduced plasma triglycerides, without altering body mass or liver lipid accumulation, consistent with phenotypes observed in human cohorts. Gene expression analysis revealed that the V227A variant enhances Ppara target gene expression in mouse liver, consistent with the effects of synthetic PPARɑ agonist treatment. Notably, V227A increased hepatic expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, suggesting that V227A enhances cardiac triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of the V227A PPARɑ variant on plasma triglycerides.
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Affiliation(s)
- Lauren F Uchiyama
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA; Department of Biological Chemistry, University of California, Los Angeles, CA
| | - Gabriel P M Ordonez
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Khoi T Pham
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - John P Kennelly
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA; Department of Biological Chemistry, University of California, Los Angeles, CA
| | - Maykel López Rodríguez
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA; Department of Biological Chemistry, University of California, Los Angeles, CA
| | - Lany Tran
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA; Department of Biological Chemistry, University of California, Los Angeles, CA
| | - Alexander Nguyen
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
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18
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Régnier M, Polizzi A, Fougeray T, Fougerat A, Perrier P, Anderson K, Lippi Y, Smati S, Lukowicz C, Lasserre F, Fouche E, Huillet M, Rives C, Tramunt B, Naylies C, Garcia G, Rousseau-Bacquié E, Bertrand-Michel J, Canlet C, Chevolleau-Mege S, Debrauwer L, Heymes C, Burcelin R, Levade T, Gourdy P, Wahli W, Blum Y, Gamet-Payrastre L, Ellero-Simatos S, Guillermet-Guibert J, Hawkins P, Stephens L, Postic C, Montagner A, Loiseau N, Guillou H. Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. PLoS Biol 2025; 23:e3003112. [PMID: 40228209 PMCID: PMC12021288 DOI: 10.1371/journal.pbio.3003112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 04/24/2025] [Accepted: 03/12/2025] [Indexed: 04/16/2025] Open
Abstract
Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression in health and in metabolic dysfunction-associated steatotic liver disease (MASLD). The absence of hepatocyte PI3Kα reduced maximal insulin-induced PI3K activity and signaling, promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110α in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.
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Affiliation(s)
- Marion Régnier
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Tiffany Fougeray
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Prunelle Perrier
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Karen Anderson
- The Signaling Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Yannick Lippi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Sarra Smati
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Céline Lukowicz
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Frédéric Lasserre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Edwin Fouche
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Marine Huillet
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Clémence Rives
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Blandine Tramunt
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
- Diabetology Department, CHU de Toulouse, Toulouse, France
| | - Claire Naylies
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Géraldine Garcia
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Elodie Rousseau-Bacquié
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Justine Bertrand-Michel
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
- Metatoul-Lipidomic Facility, MetaboHUB, Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
| | - Cécile Canlet
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Sylvie Chevolleau-Mege
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Laurent Debrauwer
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Christophe Heymes
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
| | - Rémy Burcelin
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
| | - Thierry Levade
- Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm U1037, CNRS U5071, Université de Toulouse, Toulouse, France
- Laboratoire de Biochimie, CHU de Toulouse, Toulouse, France
| | - Pierre Gourdy
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
- Diabetology Department, CHU de Toulouse, Toulouse, France
| | - Walter Wahli
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland
| | - Yuna Blum
- Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) – UMR6290, ERL U1305, Rennes, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Julie Guillermet-Guibert
- Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm U1037, CNRS U5071, Université de Toulouse, Toulouse, France
| | - Phillip Hawkins
- The Signaling Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Len Stephens
- The Signaling Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Catherine Postic
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Alexandra Montagner
- Institut des Maladies Métaboliques et Cardiovasculaires, I2MC, Université de Toulouse, Inserm, Toulouse, France
| | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France
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19
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You M, Zhou L, Wu F, Zhang L, Zhu SX, Zhang HX. Probiotics for the treatment of hyperlipidemia: Focus on gut-liver axis and lipid metabolism. Pharmacol Res 2025; 214:107694. [PMID: 40068270 DOI: 10.1016/j.phrs.2025.107694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/19/2025] [Accepted: 03/07/2025] [Indexed: 03/23/2025]
Abstract
Hyperlipidemia, a metabolic disorder marked by dysregulated lipid metabolism, is a key contributor to the onset and progression of various chronic diseases. Maintaining normal lipid metabolism is critical for health, as disruptions lead to dyslipidemia. The gut and liver play central roles in lipid homeostasis, with their bidirectional communication, known as the gut-liver axis, modulated by bile acids (BAs), gut microbiota, and their metabolites. BAs are essential for regulating their own synthesis, lipid metabolism, and anti-inflammatory responses, primarily through the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Available evidence suggests that high-fat diet-induced the gut microbiota dysbiosis can induce "leaky gut," allowing toxic microbial metabolites to enter the liver via portal circulation, triggering liver inflammation and lipid metabolism disturbances, ultimately leading to hyperlipidemia. Extensive studies have highlighted the roles of probiotics and Traditional Chinese Medicine (TCM) in restoring gut-liver axis balance and modulating lipid metabolism through regulating the levels of lipopolysaccharides, short-chain fatty acids, and BAs. However, the therapeutic potential of probiotics and TCM for hyperlipidemia remains unclear. Here, firstly, we explore the intricate interplay among gut microbiota and metabolites, lipid metabolism, gut-liver axis, and hyperlipidemia. Secondly, we summarize the mechanisms by which probiotics and TCM can alleviate hyperlipidemia by altering the composition of gut microbiota and regulating lipid metabolism via the gut-liver axis. Finally, we emphasize that more clinical trials of probiotics and TCM are necessary to examine their effects on lipid metabolism and hyperlipidemia.
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Affiliation(s)
- Min You
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Li Zhou
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Fan Wu
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Lei Zhang
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Shu-Xiu Zhu
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China.
| | - Hong-Xing Zhang
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China.
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20
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Dixon ED, Claudel T, Nardo AD, Riva A, Fuchs CD, Mlitz V, Busslinger G, Scharnagl H, Stojakovic T, Senéca J, Hinteregger H, Grabner GF, Kratky D, Verkade H, Zimmermann R, Haemmerle G, Trauner M. Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. J Hepatol 2025; 82:658-675. [PMID: 39357546 DOI: 10.1016/j.jhep.2024.09.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND & AIMS Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice. METHODS Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model. RESULTS ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors. CONCLUSIONS Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD. IMPACT AND IMPLICATIONS Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.
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Affiliation(s)
- Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alexander Daniel Nardo
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alessandra Riva
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Georg Busslinger
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | - Tatjana Stojakovic
- Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Austria
| | - Joana Senéca
- Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna, Vienna, Austria; Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Helga Hinteregger
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Gernot F Grabner
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Dagmar Kratky
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Henkjan Verkade
- Department of Paediatrics, University Medical Centre Groningen, Groningen, Netherlands
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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21
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Hansen D, Jensen JER, Andersen CAT, Jakobsgaard PR, Havelund J, Lauritsen L, Mandacaru S, Siersbaek M, Shackleton OL, Inoue H, Brewer JR, Schwabe RF, Blagoev B, Færgeman NJ, Salmi M, Ravnskjaer K. Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein. Cell Metab 2025; 37:971-986.e8. [PMID: 40037362 DOI: 10.1016/j.cmet.2025.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 11/26/2024] [Accepted: 01/24/2025] [Indexed: 03/06/2025]
Abstract
The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification into di- and triacylglycerols, shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy, we localized HSC PLVAP to caveolae residing along the sinusoidal lumen, supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver.
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Affiliation(s)
- Daniel Hansen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jasmin E R Jensen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Christian A T Andersen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Peter R Jakobsgaard
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jesper Havelund
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Line Lauritsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Samuel Mandacaru
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Majken Siersbaek
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Oliver L Shackleton
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan
| | - Jonathan R Brewer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Nils J Færgeman
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Marko Salmi
- MediCity Research Laboratory, University of Turku, 20014 Turku, Finland; Institute of Biomedicine, University of Turku, 20014 Turku, Finland; InFLAMES Research Flagship Centre, University of Turku, 20014 Turku, Finland
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark.
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22
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Miranda JP, Gana JC, Alberti G, Galindo K, Pereira A, Santos JL. Circulating Bilirubin Levels, but Not Their Genetic Determinants, Are Inversely Associated with Steatotic Liver Disease in Adolescents. Int J Mol Sci 2025; 26:2980. [PMID: 40243597 PMCID: PMC11988633 DOI: 10.3390/ijms26072980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/17/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
Epidemiologic studies suggest that elevated plasma unconjugated bilirubin confer protection against steatotic liver disease (SLD) in adults. However, evidence supporting this protective role in adolescents remains limited. We aimed to assess the association between serum bilirubin levels and their genetic determinants in protecting against SLD in Chilean adolescents. We conducted a cross-sectional study with 704 adolescents aged 15.4 ± 1 years (52% girls) of the Chilean Growth and Obesity Cohort Study. Ultrasonography echogenicity was used to diagnose SLD. We measured Z-scores of body mass index (z-BMI), total bilirubin (TB), and the genetic determinants of bilirubin (including rs887829 genotypes of UGT1A1 and bilirubin polygenic scores). Multiple logistic regression models evaluated the associations between standardized TB and its genetic determinants with SLD. We found that 1-SD of standardized plasma TB was significantly associated with a 30% reduction in the likelihood of SLD after adjustment by sex, age, z-BMI, and ethnicity (OR = 0.7; 95% CI = 0.50-0.96; p = 0.03). No significant associations were found among the rs887829 genotypes, bilirubin polygenic scores, and SLD in logistic regression models adjusted by covariates. Increased circulating bilirubin levels are unlikely causally associated with protection against SLD, and the cross-sectional association could be due to unmeasured confounding.
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Affiliation(s)
- José Patricio Miranda
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
- PhD Program in Epidemiology, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile & Universidad de Chile, Santiago 8331150, Chile
| | - Juan Cristóbal Gana
- Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Gigliola Alberti
- Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Karen Galindo
- MSc Program in Nutrition, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Ana Pereira
- Instituto de Nutrición y Tecnología de los Alimentos INTA, Universidad de Chile, Macul 7830490, Chile
| | - José Luis Santos
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
- PhD Program in Epidemiology, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Department of Health Sciences, Institute for Sustainability and Food Chain Innovation (IS-FOOD), Public University of Navarre, 31006 Pamplona, Spain
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23
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Zhang W, Guo J, Miao G, Chen J, Xu Y, Lai P, Zhang L, Han Y, Lam SM, Shui G, Wang Y, Huang W, Xian X. Fat-1 Ameliorates Metabolic Dysfunction-Associated Fatty Liver Disease and Atherosclerosis through Promoting the Nuclear Localization of PPARα in Hamsters. RESEARCH (WASHINGTON, D.C.) 2025; 8:0577. [PMID: 40052160 PMCID: PMC11884683 DOI: 10.34133/research.0577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 03/09/2025]
Abstract
Fat-1, an enzyme encoded by the fat-1 gene, is responsible for the conversion of endogenous omega-6 polyunsaturated fatty acids into omega-3 polyunsaturated fatty acids in Caenorhabditis elegans. To better investigate whether the expression of Fat-1 will exert a beneficial function in dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), we established an adeno-associated virus 9 expressing Fat-1. We found that adeno-associated-virus-mediated expression of Fat-1 markedly reduced the levels of plasma triglycerides and total cholesterol but increased high-density lipoprotein levels in male wild-type hamsters on both chow diet and high-fat diet as well as in chow-diet-fed male LDLR-/- hamsters. Fat-1 ameliorated diet-induced MAFLD in wild-type hamsters by enhancing fatty acid oxidation through the hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent pathway. Mechanistically, Fat-1 increased the levels of multiple lipid derivatives as ligands for PPARα and simultaneously facilitated the nuclear localization of PPARα. Our results provide new insights into the multiple therapeutic potentials of Fat-1 to treat dyslipidemia, MAFLD, and atherosclerosis.
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Affiliation(s)
- Wenxi Zhang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Jiabao Guo
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Guolin Miao
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Jingxuan Chen
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Yitong Xu
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Pingping Lai
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Lianxin Zhang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Yufei Han
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
- LipidALL Technologies Company Limited, Changzhou 213022, Jiangsu Province, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology,
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuhui Wang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Wei Huang
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
| | - Xunde Xian
- Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences,
Peking University, Beijing 100191, China
- Beijing Key Laboratory of Cardiovascular Receptors Research,
Peking University Third Hospital, Beijing 100191, China
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24
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Saito S, Cao DY, Bernstein EA, Shibata T, Jones AE, Rios A, Hoshi AO, Stotland AB, Nishi EE, Van Eyk JE, Divakaruni A, Khan Z, Bernstein KE. Peroxisome proliferator-activated receptor alpha is an essential factor in enhanced macrophage immune function induced by angiotensin-converting enzyme. Cell Mol Immunol 2025; 22:243-259. [PMID: 39910334 PMCID: PMC11868401 DOI: 10.1038/s41423-025-01257-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 01/12/2025] [Indexed: 02/07/2025] Open
Abstract
Increased expression of angiotensin-converting enzyme (ACE) by myeloid lineage cells strongly increases the immune activity of these cells, as observed in ACE10/10 mice, which exhibit a marked increase in antitumor and antibactericidal immunity. We report that peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that regulates genes critical for lipid metabolism, is a key molecule in the enhanced macrophage function induced by ACE. Here, we used a Cre-LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARα expression is selectively suppressed. These mice, termed A10-PPARα-Cre, have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages, resulting in reduced tumor antigen-specific CD8+ T-cell generation. Additionally, the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice, such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection. THP-1 cells expressing increased ACE (termed THP-1-ACE) constitute a human macrophage model with increased PPARα that shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA. RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance. In contrast, the in vivo administration of pemafibrate, a specific agonist of PPARα, to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%, respectively, but pemafibrate reduced tumors by 57.8% in ACE10/10 mice. With pemafibrate, the number of antitumor CD8+ T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice. We conclude that PPARα is important in the immune system of myeloid cells, including wild-type cells, and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.
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Affiliation(s)
- Suguru Saito
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Duo-Yao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ellen A Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Tomohiro Shibata
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anthony E Jones
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Amy Rios
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Aoi O Hoshi
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Aleksandr B Stotland
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Erika E Nishi
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Physiology, São Paulo School of Medicine, Universidade Federal de São Paulo, Sao Paulo, Brazil
| | - Jennifer E Van Eyk
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ajit Divakaruni
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Zakir Khan
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kenneth E Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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25
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Antwi MB, Lefere S, Clarisse D, Koorneef L, Heldens A, Onghena L, Decroix K, Fijalkowska D, Thommis J, Hellemans M, Hoorens A, Geerts A, Devisscher L, De Bosscher K. PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression. Metabolism 2025; 164:156128. [PMID: 39743041 DOI: 10.1016/j.metabol.2024.156128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD. METHODS The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers. RESULTS The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus. CONCLUSION Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD. IMPACT AND IMPLICATIONS Our research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPARα activity while diminishing ERRα activity. With PPARα agonists already tested in phase III clinical trials, ERRα ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.
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Affiliation(s)
- Milton Boaheng Antwi
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium; Department for Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology unit, Ghent University, Ghent, Belgium
| | - Sander Lefere
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium
| | - Dorien Clarisse
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Lisa Koorneef
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Anneleen Heldens
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium
| | - Louis Onghena
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium
| | - Kylian Decroix
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Department for Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology unit, Ghent University, Ghent, Belgium
| | - Daria Fijalkowska
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Jonathan Thommis
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Madeleine Hellemans
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Anne Hoorens
- Department of Pathology, Ghent University Hospital, Ghent University, 9000 Ghent, Belgium
| | - Anja Geerts
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Hepatology Research Unit, Department Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Belgium
| | - Lindsey Devisscher
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Department for Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology unit, Ghent University, Ghent, Belgium
| | - Karolien De Bosscher
- Translational Nuclear Receptor Research, UGent Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium.
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26
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Meng D, Chang M, Dai X, Kuang Q, Wang G. GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling. Free Radic Biol Med 2025; 229:312-332. [PMID: 39341301 DOI: 10.1016/j.freeradbiomed.2024.09.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/15/2024] [Accepted: 09/25/2024] [Indexed: 10/01/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro. Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8HKO) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.
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Affiliation(s)
- Dongxiao Meng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, PR China
| | - Minghui Chang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, PR China
| | - Xianling Dai
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Qin Kuang
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Guangchuan Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, PR China.
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27
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Amiri P, Hosseini SA, Saghafi-Asl M, Roshanravan N, Tootoonchian M. Expression of PGC-1α, PPAR-α and UCP1 genes, metabolic and anthropometric factors in response to sodium butyrate supplementation in patients with obesity: a triple-blind, randomized placebo-controlled clinical trial. Eur J Clin Nutr 2025; 79:249-257. [PMID: 39448815 DOI: 10.1038/s41430-024-01512-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 09/04/2024] [Accepted: 09/16/2024] [Indexed: 10/26/2024]
Abstract
OBJECTIVES There is increasing evidence that gut metabolites have a role in the etiology of obesity. This study aimed to investigate the effects of sodium butyrate (NaB) supplementation on the expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α), PPAR-α, and uncoupling protein-1 (UCP-1) genes, as well as on the metabolic parameters and anthropometric indices in persons with obesity. METHODS In this triple-blind placebo-controlled randomized clinical trial, 50 individuals with obesity were randomly assigned to NaB (600 mg/day) + hypo-caloric diet or placebo group + hypo-caloric diet for 8 weeks. The study measured the participants' anthropometric characteristics, food consumption, and feelings of hunger in addition to the serum levels of metabolic indices and the mRNA expression of the PGC-1α, PPAR-α, and UCP-1 genes in peripheral blood mononuclear cells (PBMCs). RESULTS PGC-1α and UCP-1 genes expression significantly increased in NaB group compared to the placebo at the endpoint. A significant decrease in weight, BMI, and waist circumference (WC) was observed in NaB group. Among the metabolic factors, NaB significantly decreased fasting blood sugar (FBS) (P = 0.04), low-density lipoprotein cholesterol (LDL-C) (P = 0.038) and increased high-density lipoprotein cholesterol (HDL-C) (P = 0.016). NaB could not significantly change serum GLP-1 level. CONCLUSIONS This study unveiled NaB supplementation alone cannot have significant beneficial effects on anthropometric, and biochemical factors. NaB could affect anthropometric and metabolic risk variables associated with obesity only when prescribed, along with calorie restriction. CLINICAL TRIAL REGISTRATION This study was registered in the Iranian Registry of Clinical Trials ( https://en.irct.ir/trial/53968 ) on 31 January 2021 (registry number IRCT20190303042905N2).
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Affiliation(s)
- Parichehr Amiri
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Nutrition and Metabolic Diseases Research Center, Clinical Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Ahmad Hosseini
- Nutrition and Metabolic Diseases Research Center, Clinical Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Maryam Saghafi-Asl
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mitra Tootoonchian
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Moolsup F, Suttithumsatid W, Woonnoi W, Chonpathompikunlert P, Tanasawet S, Sukketsiri W. Passion Fruit Seed Extract Attenuates Hepatic Steatosis in Oleic Acid-Treated HepG2 Cells through Modulation of ERK1/2 and Akt Signaling Pathways. Cell Biochem Biophys 2025:10.1007/s12013-025-01706-5. [PMID: 40025286 DOI: 10.1007/s12013-025-01706-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2025] [Indexed: 03/04/2025]
Abstract
Hepatic steatosis, commonly referred to as fatty liver disease, is defined by the abnormal buildup of fat within liver cells. Currently, primary treatments mainly focus on lifestyle changes, underscoring a lack of direct pharmacological options. Passion fruit seed extract (PFSE) has been reported to decrease hepatosteatosis; however, the mechanism underlying this effect has not been clarified. Therefore, the objective of this research was to investigate the effects and mechanisms of action of PFSE against oleic acid (OA)-induced hepatosteatosis in HepG2 cells. OA-induced HepG2 cells were analyzed by using various cell-based experiments, including assessments of cytotoxicity, reactive oxygen species (ROS) production, apoptosis, and protein and gene expression. LC-MS-MS analysis showed that PFSE contains a variety of phytochemical compounds such as alkaloids, flavonoids, stilbenoids, coumarins, terpenoids, lipids, and fatty acid derivatives, which have the potential to exhibit various pharmacological activities. In this study, PFSE demonstrated antioxidant, anti-inflammatory, and lipid metabolism-regulating activities. It also influenced key genes related to lipid metabolism, including SREBP-1c, ACC, FASN, PPARα, CPT-1A, LPL, SCD1, and LDLR. The positive effects of PFSE on OA-induced hepatic steatosis in HepG2 cells were modulated through the Akt and ERK signaling pathways, suggesting that PFSE may offer a comprehensive approach to managing hepatic steatosis.
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Affiliation(s)
- Furoida Moolsup
- Laboratory Animal Service Center, Faculty of Science, Prince of Songkla University, Songkhla, Thailand
| | - Wiwit Suttithumsatid
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand
- Phytomedicine and Pharmaceutical Biotechnology Excellence Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Thailand
| | - Wanwipha Woonnoi
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Pennapa Chonpathompikunlert
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Pathumthani, Thailand
| | - Supita Tanasawet
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Wanida Sukketsiri
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
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29
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Cui YF, Chen XC, Mijiti T, Abudurusuli A, Deng LH, Ma X, Chen B. PCSK9 with a gain of function D374Y mutation aggravates atherosclerosis by inhibiting PPARα expression. Sci Rep 2025; 15:6941. [PMID: 40011664 PMCID: PMC11865302 DOI: 10.1038/s41598-025-91061-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 02/18/2025] [Indexed: 02/28/2025] Open
Abstract
The preprotein convertase, Bacillus subtilis protease/kexin type 9 serine protease (PCSK9), has garnered significant attention as a potential lipid lowering and therapeutic drug target for atherosclerosis (AS). Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in various tissues and has crucial roles in lipid metabolism and the inflammatory response; however, the precise impact of PCSK9 on AS progression through its regulation of PPARα remains uncertain. The present study aimed to examine the impact of introducing stable liver transduction of human derived PCSK9 with a gain of function D374Y mutation (PCSK9DY) into systemic PPARα knockout mice (PPARα-/-) on plasma lipid levels and AS. Enzymatic assays were employed to evaluate plasma lipid concentrations at various time points, and aortic plaque formation and the degree of inflammatory infiltration quantified. Subsequently, we validated our in vivo results using mouse primary peritoneal macrophages (MPMs). Furthermore, AAV8.2-PPARα virus vector was transduced into transgenic mice of human PCSK9(hPCSK9DY-Tg) by tail vein, and the changes of plasma lipid level and AS were detected. PCSK9DY expression exacerbated symptoms of hypercholesterolemia in PPARα-/- mice. En face analysis and quantification of aortic root sections demonstrated a significant increase in aortic plaque area and inflammatory infiltration in PCSK9DY transduced PPARα-/- mice. Secretion of inflammatory cytokines was elevated in PCSK9DY transduced PPARα-/- mice. In vitro, recombinant hPCSK9 protein promotes the foam cell formation and inflammatory cytokines secretion of PPARα-/- MPMs by increasing the expression of SR-A and TLR4/NF-κB pathway proteins. AAV8.2-PPARα virus vector can reduce the plasma lipid level and AS formation in hPCSK9DY-Tg mice. These finding demonstrate that PCSK9DY expression notably facilitated AS progression in PPARα-/- mice by increasing plasma lipid concentrations and inflammation. However, overexpression of PPARα can reduce AS formation in hPCSK9DY-Tg mice.
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Affiliation(s)
- Yuan Feng Cui
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Xiao Cui Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Tuoluonayi Mijiti
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Abidan Abudurusuli
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Li Hui Deng
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Basic Medical College, Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Xiang Ma
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Bangdang Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China.
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
- Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, 830054, China.
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Berthier A, Gheeraert C, Vinod M, Johanns M, Guille L, Haas JT, Dubois-Chevalier J, Eeckhoute J, Staels B, Lefebvre P. Unveiling the molecular legacy of transient insulin resistance: Implications for hepatic metabolic adaptability. J Hepatol 2025:S0168-8278(25)00080-7. [PMID: 39947330 DOI: 10.1016/j.jhep.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND & AIMS Insulin plays a central role in coordinating metabolic flexibility (MetF). Insulin resistance (IR) can impair MetF, contributing to type 2 diabetes and obesity. Transient IR episodes, like gestational diabetes or stress-induced hyperglycemia, also heighten the risk of later diabetes development. While the health significance of transient IR is well established, we aimed to better understand the heretofore poorly understood molecular processes that occur after such episodes. METHODS To do this, we characterized the hepatic response to a high-fat diet challenge in mice previously exposed to a transient IR episode. We integrated transcriptomic, epigenomic, lipidomic, and molecular clock assessments to provide a molecular basis for the observed dysregulations. RESULTS Our study shows that temporarily blocking the insulin receptor in young mice leads to later-life liver issues by hindering PPARα-mediated adaptation to a high-fat diet. This is linked to decreased histone active marks at PPARα sites and reduced endogenous PPARα ligands. Transient insulin receptor blockade also altered the liver's molecular clock, particularly affecting PPARα transcriptional responsiveness. CONCLUSIONS Seemingly reversible metabolic challenges in early adulthood may predispose the liver to exacerbated metabolic dysfunctions when confronted with chronic challenges later in life. IMPACT AND IMPLICATIONS While the health significance of transient insulin resistance is well established, the molecular processes that occur after such episodes are poorly understood. This study thus provides a circadian molecular paradigm for a later-in-life alteration of liver metabolic flexibility following a previous episode of insulin resistance and calls for particular attention to be paid to detecting transient episodes of insulin resistance as they occur in patients with gestational diabetes or stress-induced hyperglycemia. By extension, any transient exposure to compounds altering circadian rhythmicity, such as anti-depressants, might predispose to a compromised metabolic response to an unbalanced diet later in life.
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Affiliation(s)
- Alexandre Berthier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France.
| | - Céline Gheeraert
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Manjula Vinod
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Manuel Johanns
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Loïc Guille
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Joel T Haas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Julie Dubois-Chevalier
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Jérôme Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France
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Li Z, Wang L, Tian C, Wang Z, Zhao H, Qi Y, Chen W, Wuyun Q, Amin B, Lian D, Zhu J, Zhang N, Zheng L, Xu G. Identification of hub biomarkers in liver post-metabolic and bariatric surgery using comprehensive machine learning (experimental studies). Int J Surg 2025; 111:1814-1824. [PMID: 39728595 DOI: 10.1097/js9.0000000000002179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/16/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND The global prevalence of non-alcoholic fatty liver disease (NAFLD) is approximately 30%, and the condition can progress to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Metabolic and bariatric surgery (MBS) has been shown to be effective in treating obesity and related disorders, including NAFLD. OBJECTIVE In this study, comprehensive machine learning was used to identify biomarkers for precise treatment of NAFLD from the perspective of MBS. METHODS Differential expression and univariate logistic regression analyses were performed on lipid metabolism-related genes in a training dataset (GSE83452) and two validation datasets (GSE106737 and GSE48452) to identify consensus-predicted genes (CPGs). Subsequently, 13 machine learning algorithms were integrated into 99 combinations; among which the optimal combination was selected based on the total score of the area under the curve, accuracy, F-score, and recall in the two validation datasets. Hub genes were selected based on their importance ranking in the algorithms and the frequency of their occurrence. Finally, a mouse model of MBS was established, and the mRNA expression of the hub genes was validated via quantitative PCR. RESULTS A total of 12 CPGs were identified after intersecting the results of differential expression and logistic regression analyses on a Venn diagram. Four machine learning algorithms with the highest total scores were identified as optimal models. Additionally, PPARA, PLIN2, MED13, INSIG1, CPT1A, and ALOX5AP were identified as hub genes. The mRNA expression patterns of these genes in mice subjected to MBS were consistent with those observed in the three datasets. CONCLUSION Altogether, the six hub genes identified in this study are important for the treatment of NAFLD via MBS and hold substantial promise in guiding personalized treatment of NAFLD in clinical settings.
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Affiliation(s)
- Zhehong Li
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Liang Wang
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Chenxu Tian
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Zheng Wang
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hao Zhao
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yao Qi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Weijian Chen
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Qiqige Wuyun
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Buhe Amin
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Dongbo Lian
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Jinxia Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Nengwei Zhang
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lifei Zheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Guangzhong Xu
- Surgery Centre of Diabetes Mellitus, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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Attema B, de la Rosa Rodriguez MA, van Schothorst EM, Grefte S, Hooiveld GJ, Kersten S. Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice. Mol Metab 2025; 92:102092. [PMID: 39746607 PMCID: PMC11773045 DOI: 10.1016/j.molmet.2024.102092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/20/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025] Open
Abstract
OBJECTIVE The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking. METHODS We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47. RESULTS SLC25A47 was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47. CONCLUSION Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.
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Affiliation(s)
- Brecht Attema
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Montserrat A de la Rosa Rodriguez
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | | | - Sander Grefte
- Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands
| | - Guido Jej Hooiveld
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
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Soukop J, Kazdová L, Hüttl M, Malínská H, Marková I, Oliyarnyk O, Miklánková D, Gurská S, Rácová Z, Poruba M, Večeřa R. Beneficial Effect of Fenofibrate in Combination with Silymarin on Parameters of Hereditary Hypertriglyceridemia-Induced Disorders in an Animal Model of Metabolic Syndrome. Biomedicines 2025; 13:212. [PMID: 39857794 PMCID: PMC11763318 DOI: 10.3390/biomedicines13010212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/11/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (-77%) and free fatty acids (-29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (-35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (-34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders.
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Affiliation(s)
- Jan Soukop
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Ludmila Kazdová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Hana Malínská
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Irena Marková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Olena Oliyarnyk
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Denisa Miklánková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Soňa Gurská
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic
| | - Zuzana Rácová
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Martin Poruba
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
| | - Rostislav Večeřa
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77515 Olomouc, Czech Republic; (J.S.)
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34
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Abbas-Hashemi SA, Yari Z, Hatami B, Anushiravani A, Kolahdoozan S, Zamanian A, Akbarzadeh N, Hekmatdoost A. Caffeine supplement, inflammation, and hepatic function in cirrhotic patients: A randomized, placebo- controlled, clinical trial. Heliyon 2025; 11:e41138. [PMID: 39758360 PMCID: PMC11699412 DOI: 10.1016/j.heliyon.2024.e41138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 01/07/2025] Open
Abstract
Aim We investigated the possibility of caffeine supplementation for managing the inflammation, and hepatic function in cirrhotic patients. Methods In this randomized, double-blind, placebo-controlled trial, fifty patients with cirrhosis were randomly assigned to receive either caffeine supplement (400 mg), or placebo for eight weeks. Results The results indicated a significant decrease in AST, platelets (P = 0.002), and PTT (P < 0.001), in the caffeine group compared to the placebo group. Also, caffeine supplementation resulted in a significant reduction in inflammatory biomarkers compared to placebo (p < 0.05). A significant improvement in liver indices including AST to platelet ratio index (APRI), (P < 0.001). Fibrosis 4 score (P < 0.001), and MELD score (P = 0.034)., was observed after 8 weeks caffeine supplementation. Conclusion The results of the present study indicated that daily supplementation of 400 mg caffeine in cirrhotic patients can significantly improve liver fibrosis and reduce inflammatory factors.The trial was registered at the Iranian Registry of Clinical Trials (Registration ID: IRCT20100524004010N34).
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Affiliation(s)
- Seyed Ali Abbas-Hashemi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Amir Anushiravani
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shadi Kolahdoozan
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Zamanian
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Nadia Akbarzadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science, Tehran, Iran
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35
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Korenfeld N, Charni-Natan M, Bruse J, Goldberg D, Marciano-Anaki D, Rotaro D, Gorbonos T, Radushkevitz-Frishman T, Polizzi A, Nasereddin A, Gover O, Bar-Shimon M, Fougerat A, Guillou H, Goldstein I. Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis. Nucleic Acids Res 2025; 53:gkae1161. [PMID: 39673515 PMCID: PMC11724283 DOI: 10.1093/nar/gkae1161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/17/2024] [Accepted: 11/06/2024] [Indexed: 12/16/2024] Open
Abstract
Mammals withstand frequent and prolonged fasting periods due to hepatic production of glucose and ketone bodies. Because the fasting response is transcriptionally regulated, we asked whether enhancer dynamics impose a transcriptional program during recurrent fasting and whether this generates effects distinct from a single fasting bout. We found that mice undergoing alternate-day fasting (ADF) respond profoundly differently to a following fasting bout compared to mice first experiencing fasting. Hundreds of genes enabling ketogenesis are 'sensitized' (i.e. induced more strongly by fasting following ADF). Liver enhancers regulating these genes are also sensitized and harbor increased binding of PPARα, the main ketogenic transcription factor. ADF leads to augmented ketogenesis compared to a single fasting bout in wild-type, but not hepatocyte-specific PPARα-deficient mice. Thus, we found that past fasting events are 'remembered' in hepatocytes, sensitizing their enhancers to the next fasting bout and augment ketogenesis. Our findings shed light on transcriptional regulation mediating adaptation to repeated signals.
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Affiliation(s)
- Noga Korenfeld
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Meital Charni-Natan
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Justine Bruse
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, 180 Chemin de Tournefeuille, 31027 Toulouse, France
| | - Dana Goldberg
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Dorin Marciano-Anaki
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Dan Rotaro
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Tali Gorbonos
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Talia Radushkevitz-Frishman
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, 180 Chemin de Tournefeuille, 31027 Toulouse, France
| | - Abed Nasereddin
- Genomics Applications Laboratory, Core Research Facility, Faculty of Medicine, The Hebrew University of Jerusalem-Hadassah Medical School, Kalman Ya'Akov Man Street, Jerusalem 9112001, Israel
| | - Ofer Gover
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Meirav Bar-Shimon
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
| | - Anne Fougerat
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, 180 Chemin de Tournefeuille, 31027 Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, 180 Chemin de Tournefeuille, 31027 Toulouse, France
| | - Ido Goldstein
- Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel
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Liu JY, Kuna RS, Pinheiro LV, Nguyen PTT, Welles JE, Drummond JM, Murali N, Sharma PV, Supplee JG, Shiue M, Zhao S, Farria AT, Kumar A, Ruchhoeft ML, Demetriadou C, Kantner DS, Chatoff A, Megill E, Titchenell PM, Snyder NW, Metallo CM, Wellen KE. Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase. Cell Metab 2025; 37:239-254.e7. [PMID: 39471816 PMCID: PMC11711013 DOI: 10.1016/j.cmet.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 08/07/2024] [Accepted: 10/18/2024] [Indexed: 11/01/2024]
Abstract
ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.
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Affiliation(s)
- Joyce Y Liu
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ramya S Kuna
- Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Laura V Pinheiro
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Phuong T T Nguyen
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jaclyn E Welles
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jack M Drummond
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nivitha Murali
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Prateek V Sharma
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Julianna G Supplee
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mia Shiue
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Steven Zhao
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aimee T Farria
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Avi Kumar
- Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Mauren L Ruchhoeft
- Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Christina Demetriadou
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Daniel S Kantner
- Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Adam Chatoff
- Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Emily Megill
- Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Paul M Titchenell
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nathaniel W Snyder
- Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Christian M Metallo
- Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Bril F, Berg G, Barchuk M, Nogueira JP. Practical Approaches to Managing Dyslipidemia in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. J Lipid Atheroscler 2025; 14:5-29. [PMID: 39911965 PMCID: PMC11791423 DOI: 10.12997/jla.2025.14.1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/15/2024] [Accepted: 03/10/2024] [Indexed: 02/07/2025] Open
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gabriela Berg
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Magali Barchuk
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina
- Universidad Internacional de las Américas, San José, Costa Rica
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Cai Y, Fang L, Chen F, Zhong P, Zheng X, Xing H, Fan R, Yuan L, Peng W, Li X. Targeting AMPK related signaling pathways: A feasible approach for natural herbal medicines to intervene non-alcoholic fatty liver disease. J Pharm Anal 2025; 15:101052. [PMID: 40034684 PMCID: PMC11873010 DOI: 10.1016/j.jpha.2024.101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 07/13/2024] [Accepted: 07/22/2024] [Indexed: 03/05/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by abnormal deposition of lipid in hepatocytes. If not intervened in time, NAFLD may develop into liver fibrosis or liver cancer, and ultimately threatening life. NAFLD has complicated etiology and pathogenesis, and there are no effective therapeutic means and specific drugs. Currently, insulin sensitizers, lipid-lowering agents and hepatoprotective agents are often used for clinical intervention, but these drugs have obvious side effects, and their effectiveness and safety need to be further confirmed. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in maintaining energy homeostasis. Activated AMPK can enhance lipid degradation, alleviate insulin resistance (IR), suppress oxidative stress and inflammatory response, and regulate autophagy, thereby alleviating NAFLD. Natural herbal medicines have received extensive attention recently because of their regulatory effects on AMPK and low side effects. In this article, we reviewed the biologically active natural herbal medicines (such as natural herbal medicine formulas, extracts, polysaccharides, and monomers) that reported in recent years to treat NAFLD via regulating AMPK, which can serve as a foundation for subsequent development of candidate drugs for NAFLD.
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Affiliation(s)
- Yongqing Cai
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Lu Fang
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Fei Chen
- Department of Pharmacy, Dazhou Integrated Traditional Chinese Medicine and Western Medicine Hospital, Dazhou, Sichuan, 635000, China
| | - Peiling Zhong
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Xiangru Zheng
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Haiyan Xing
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Rongrong Fan
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14152, Sweden
| | - Lie Yuan
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Xiaoli Li
- Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China
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Li G, Hu Y, Zhao H, Peng Z, Shang X, Zhang J, Xie K, Li M, Zhou X, Zhou Q, Li K, Zhou F, Wang H, Xu Z, Liu J, Sun P. Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409126. [PMID: 39611414 PMCID: PMC11744575 DOI: 10.1002/advs.202409126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti-gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity-specific DILI warrants further investigation. In this study, through a combined multi-omics, pharmacological, and pharmacokinetic approaches, it is found that BBR-induced obesity-specific DILI is primarily through the potentiation of peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism-driven amplification of hepatic PPARγ agonism mediates BBR-induced obesity-specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre-existing NAFLD in both clinical practice and drug discovery processes.
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Affiliation(s)
- Guanting Li
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Yourong Hu
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Han Zhao
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Ziyu Peng
- State Key Laboratory of Drug ResearchDrug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China
| | - Xin Shang
- Key Laboratory of Drug Metabolism and PharmacokineticsState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing210009China
| | - Jia Zhang
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Kunxin Xie
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Meiwei Li
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Xiaohang Zhou
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Qinyao Zhou
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Kai Li
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and PharmacokineticsState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing210009China
| | - Heyao Wang
- State Key Laboratory of Drug ResearchDrug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China
| | - Zhijian Xu
- State Key Laboratory of Drug ResearchDrug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China
| | - Jiali Liu
- Key Laboratory of Drug Metabolism and PharmacokineticsState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing210009China
| | - Peng Sun
- The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityWuxi People's HospitalWuxi Medical CenterKey Laboratory of Human Functional Genomics of Jiangsu ProvinceDepartment of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing211166China
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Mijiti T, Chen X, Ma X, Ma Y, Ma X, Chen B. Inhibition of hepatic PCSK9 as a novel therapeutic target ameliorates metabolic steatohepatitis in mice. Int Immunopharmacol 2024; 143:113621. [PMID: 39549549 DOI: 10.1016/j.intimp.2024.113621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/07/2024] [Accepted: 11/09/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND & AIMS Metabolic steatohepatitis (MASH) is closely related to metabolic disorders, and the main characteristics of MASH are hepatocyte steatosis with hepatocyte injury and inflammation. In severe cases, MASH can develop into liver cirrhosis. At present, there is no effective treatment for MASH. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a popular target for the development of cholesterol-lowering drugs and therapeutic interventions for cardiovascular disease. The present study aimed to explore the role of PCSK9 in methionine- and choline-deficient (MCD) diet-induced MASH progression and its targeted intervention. METHODS PCSK9 expression was determined in a MASH mouse model, and the role of PCSK9 in the regulation of lipid metabolism, inflammation, and fibrosis was investigated using PCSK9 knockout (PCSK9-/-) mice fed a MCD diet. An adeno-associated virus was used to alter PCSK9 expression in MASH mice. RESULTS Following the MCD diet, C57BL/6J wild-type (WT) mice developed marked steatohepatitis and elevated hepatic PCSK9 expression, and circulating PCSK9 expression. PCSK9-/- mice showed significantly alleviated MCD-induced hepatic steatosis, with lower serum ALT levels, lower serum AST levels, smaller hepatic vacuoles, and less hepatic lipid deposition. PCSK9-/- mice on the MCD diet showed a significantly reduced levels of inflammation and fibrogenesis. Moreover, adeno-associated virus (AAV)-mediated PCSK9 silencing in mouse livers significantly relieved liver steatosis, inflammation, and fibrosis. CONCLUSIONS The present study demonstrated an important role of PCSK9 in MASH, suggesting that inhibition of PCSK9 may represent a novel and effective therapeutic strategy for MASH treatment.
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Affiliation(s)
- Tuoluonayi Mijiti
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Xiaocui Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiang Ma
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yitong Ma
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiumin Ma
- Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
| | - Bangdang Chen
- Xinjiang Key Laboratory of Cardiovascular Disease Research, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; Basic Medical College, Xinjiang Medical University, Urumqi, Xinjiang, China.
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Perry AS, Hadad N, Chatterjee E, Jimenez-Ramos M, Farber-Eger E, Roshani R, Stolze LK, Betti MJ, Zhao S, Huang S, Martens L, Kendall TJ, Thone T, Amancherla K, Bailin S, Gabriel CL, Koethe J, Carr JJ, Terry JG, Vaitinadin NS, Freedman JE, Tanriverdi K, Alsop E, Van Keuren-Jensen K, Sauld JFK, Mahajan G, Khan SS, Colangelo L, Nayor M, Fisher-Hoch S, McCormick JB, North KE, Below JE, Wells QS, Abel ED, Kalhan R, Scott C, Guilliams M, Gamazon ER, Fallowfield JA, Banovich NE, Das S, Shah R. A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver. Cell Rep Med 2024; 5:101871. [PMID: 39657669 PMCID: PMC11722105 DOI: 10.1016/j.xcrm.2024.101871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/06/2024] [Accepted: 11/18/2024] [Indexed: 12/12/2024]
Abstract
Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications.
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Affiliation(s)
- Andrew S Perry
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Niran Hadad
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Emeli Chatterjee
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Maria Jimenez-Ramos
- Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | | | - Rashedeh Roshani
- Vanderbilt Genetics Institute, Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Michael J Betti
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Shilin Zhao
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Shi Huang
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Liesbet Martens
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Timothy J Kendall
- Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - Tinne Thone
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | | | - Samuel Bailin
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Curtis L Gabriel
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - John Koethe
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - J Jeffrey Carr
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | | | - Jane E Freedman
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Eric Alsop
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | | | | | - Sadiya S Khan
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Laura Colangelo
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Matthew Nayor
- Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Susan Fisher-Hoch
- School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, USA
| | - Joseph B McCormick
- School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, USA
| | - Kari E North
- CVD Genetic Epidemiology Computational Laboratory, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Jennifer E Below
- Vanderbilt Genetics Institute, Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quinn S Wells
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | - E Dale Abel
- Department of Medicine, David Geffen School of Medicine and UCLA Health, University of California-Los Angeles, Los Angeles, CA, USA
| | - Ravi Kalhan
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Charlotte Scott
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Martin Guilliams
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Eric R Gamazon
- Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | | | - Saumya Das
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
| | - Ravi Shah
- Vanderbilt University School of Medicine, Nashville, TN, USA.
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Jiang S, Fan X, Hua J, Liu S, Feng Y, Shao D, Shen Y, Wang Z, Yan X, Wang J. Integrated metabolomics and network pharmacology analysis to reveal the protective effect of Complanatoside A on nonalcoholic fatty liver disease. Eur J Pharmacol 2024; 985:177074. [PMID: 39481627 DOI: 10.1016/j.ejphar.2024.177074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/11/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
INTRODUCTION The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo. METHODS First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound-target networks and validated by molecular docking and western blotting. RESULTS CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets. CONCLUSION This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD.
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Affiliation(s)
- Sijia Jiang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Xiaoxu Fan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Jian Hua
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Shuangqiao Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Yingtong Feng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Danyue Shao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Yiwei Shen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Zhen Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China
| | - Xuehua Yan
- Institute of Traditional Chinese Medicine, Xinjiang Medical University, 830011, Urumqi, China.
| | - Jingxia Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 102488, Beijing, China.
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Wang S, Yin J, Liu Z, Liu X, Tian G, Xin X, Qin Y, Feng X. Metabolic disorders, inter-organ crosstalk, and inflammation in the progression of metabolic dysfunction-associated steatotic liver disease. Life Sci 2024; 359:123211. [PMID: 39491769 DOI: 10.1016/j.lfs.2024.123211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/20/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health concern, affecting over 30 % of adults. It is a principal driver in the development of cirrhosis and hepatocellular carcinoma. The complex pathogenesis of MASLD involves an excessive accumulation of lipids, subsequently disrupting lipid metabolism and prompting inflammation within the liver. This review synthesizes the recent research progress in understanding the mechanisms contributing to MASLD progression, with particular emphasis on metabolic disorders and interorgan crosstalk. We highlight the molecular mechanisms linked to these factors and explore their potential as novel targets for pharmacological intervention. The insights gleaned from this article have important implications for both the prevention and therapeutic management of MASLD.
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Affiliation(s)
- Shendong Wang
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Junhao Yin
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Zhaojun Liu
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Xin Liu
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Ge Tian
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271000, China
| | - Xijian Xin
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Yiming Qin
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China
| | - Xiujing Feng
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan 250117, Shandong, China.
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Taghizadeh M, Maleki MH, Vakili O, Tavakoli R, Zarei P, Dehghanian A, Bordbar H, Shafiee SM. Bilirubin, a hepatoprotective agent that activates SIRT1, PGC-1α, and PPAR-α, while inhibiting NF-κB in rats with metabolic-associated fatty liver disease. Sci Rep 2024; 14:29244. [PMID: 39587213 PMCID: PMC11589846 DOI: 10.1038/s41598-024-80119-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/15/2024] [Indexed: 11/27/2024] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by fatty liver disease alongside overweight or obesity and/or type 2 diabetes mellitus (T2DM). Timely intervention is crucial for a potential cure. This study aimed to investigate the effects of bilirubin, an endogenous antioxidant, on lipid metabolism and inflammation in MAFLD. Specifically, it examined bilirubin's impact on SIRT1, PPAR-α, and NF-κB in the livers of rats with MAFLD induced by a high-fat diet (HFD) and streptozotocin (STZ) administration. Forty eight-week adult male Sprague Dawley rats were divided into five groups (n = 8): Control, HFD-STZ, HFD-S-BR6, HFD-S-BR14, and C-BR14. In the last three groups, bilirubin administration was performed intraperitoneally for 6 and 14 weeks (10 mg/kg/day). We selected the key genes associated with MAFLD and subsequently performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses to explore the enriched biological processes and signaling pathways. Hence, the gene expression of SIRT1, PGC-1α, PPAR-α, and inflammatory genes (NF-κB, TNF-α, IL-6, and IL-1β) was measured using Real-time quantitative PCR. Stereological and histopathological alterations of liver structure as well as lipid profile, biochemical indices, and liver indices, were also assessed among different groups. The enrichment analysis identified that several signaling pathways and biological processes might be related to MAFLD. Bilirubin-treated rats contained higher PPAR-α, PGC-1α, and SIRT1 expression levels by approximately 5.7-, 2.1-, and 2.2-fold, respectively, compared to the HFD-receiving rats (p < 0.0001, p < 0.05, and p < 0.05). Whereas, the genes involved in the inflammatory cascades, including NF-κB, TNF-α, and IL-6, were downregulated by 0.6-fold (p < 0.05) following 14-week treatment of bilirubin, while only significantly decreased expression of NF-κB and IL-6 (approximately 0.6-fold, p < 0.05) were observed after 6-week treatment of bilirubin. Remarkably, bilirubin administration favorably reversed the effects of HFD on the liver's volume and cell numbers and ameliorated the related structural changes. It also improved lipid profile, biochemical parameters, and liver indices of HFD-STZ rats. This study indicated that bilirubin acts as a protective/ameliorative compound against MAFLD, particularly through regulating the key genes involved in lipid metabolism and inflammation in HFD-STZ rats.
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Affiliation(s)
- Motahareh Taghizadeh
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Maleki
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ramin Tavakoli
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parvin Zarei
- Department of Bioinformatics, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirreza Dehghanian
- Trauma Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Pathology and Cytogenetics Division, Department of Pathology, School of Medicine, Shiraz University, Shiraz, Iran
| | - Hossein Bordbar
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Jiang M, Feng Y, Wang J, Xu X, Liu Z, Li T, Ma S, Wang Y, Guo X, Du S. Saikogenin A improves ethanol-induced liver injury by targeting SIRT1 to modulate lipid metabolism. Commun Biol 2024; 7:1547. [PMID: 39572758 PMCID: PMC11582619 DOI: 10.1038/s42003-024-07234-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024] Open
Abstract
Chronic alcohol consumption can lead to alcohol live disease (ALD). Steatosis is a critical hallmark of ALD, making it an important stage for therapeutic intervention. Saikosaponin A (SSa), a compound found in Radix Bupleuri, has previously shown promising hepatoprotective, anti-inflammatory, and antioxidant properties. However, its role in ALD remains understudied. We employ cell-based screening models and a chronic-plus-binge ethanol-fed mouse model to investigate the protective mechanisms of SSa and its metabolite Saikogenin A (SGA), against ethanol-induced hepatocyte injury. Our RNA-seq analysis in mice unveils that SSa primarily acts through the mTOR and PPAR-α signaling pathways in the liver. Biophysical assays and loss of function experiments confirm SGA directly binds to and modulates the activity of SIRT1 protein, mitigating ethanol-induced cell injury via the SIRT1-mTOR-PPAR-α axis. Furthermore, SGA displays a survival prolonging advantage compared to resveratrol for treating ALD. This suggests SGA holds promise as a potential therapeutic agent for ALD.
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Affiliation(s)
- Mingzhu Jiang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ying Feng
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
| | - Jingxian Wang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
| | - Xiang Xu
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
| | - Zegan Liu
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Tongfei Li
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
| | - Shinan Ma
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China
| | - Yufeng Wang
- Institute for Systems Genetics, New York University, New York, NY, USA.
| | - Xingrong Guo
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China.
| | - Shiming Du
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of neurosurgery, Taihe Hospital, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, China.
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
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Masenga SK, Desta S, Hatcher M, Kirabo A, Lee DL. How PPAR-alpha mediated inflammation may affect the pathophysiology of chronic kidney disease. Curr Res Physiol 2024; 8:100133. [PMID: 39665027 PMCID: PMC11629568 DOI: 10.1016/j.crphys.2024.100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/03/2024] [Accepted: 11/12/2024] [Indexed: 12/13/2024] Open
Abstract
Chronic kidney disease (CKD) is a major risk factor for death in adults. Inflammation plays a role in the pathogenesis of CKD, but the mechanisms are poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor and one of the three members (PPARα, PPARβ/δ, and PPARγ) of the PPARs that plays an important role in ameliorating pathological processes that accelerate acute and chronic kidney disease. Although other PPARs members are well studied, the role of PPAR-α is not well described and its role in inflammation-mediated chronic disease is not clear. Herein, we review the role of PPAR-α in chronic kidney disease with implications for the immune system.
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Affiliation(s)
- Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Zambia
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Selam Desta
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Mark Hatcher
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dexter L. Lee
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
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Małodobra-Mazur M, Ołdakowska M, Dobosz T. Exploring PPAR Gamma and PPAR Alpha's Regulation Role in Metabolism via Epigenetics Mechanism. Biomolecules 2024; 14:1445. [PMID: 39595621 PMCID: PMC11591816 DOI: 10.3390/biom14111445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/18/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to a family of nuclear receptors. To date, three types of PPARs, namely PPARα, PPARδ, and PPARγ, have been identified, demonstrating co-expression across numerous tissues. PPARγ is primarily distributed in adipose tissue, the colon, the immune system, and the retina, while PPARα is predominantly expressed in metabolic tissues such as brown adipose tissue, the liver, and the kidneys. Both PPARγ and PPARα play crucial roles in various cellular processes. Recent data suggest that the PPAR family, among other mechanisms, might also be regulated by epigenetic mechanisms. Our recent studies, alongside numerous others, have highlighted the pivotal roles of DNA methylation and histone modifications in the regulation of PPARγ and PPARα, implicating them in the deterioration of metabolic disorders via epigenetic mechanisms. This still not fully understood mechanism of regulation in the nuclear receptors family has been summarized and described in the present paper. The present review summarizes the available data on PPARγ and PPARα regulation via epigenetic mechanisms, elucidating the link between the development of metabolic disorders and the dysregulation of PPARγ and PPARα resulting from these mechanisms.
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Affiliation(s)
- Małgorzata Małodobra-Mazur
- Department of Forensic Science, Division of Molecular Techniques, Wroclaw Medical University, Sklodowskiej-Curie 52, 51-367 Wroclaw, Poland; (M.O.); (T.D.)
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48
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Qi F, Li T, Deng Q, Fan A. The impact of aerobic and anaerobic exercise interventions on the management and outcomes of non-alcoholic fatty liver disease. Physiol Res 2024; 73:671-686. [PMID: 39530904 PMCID: PMC11629946 DOI: 10.33549/physiolres.935244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 06/25/2024] [Indexed: 12/13/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder that includes non-alcoholic hepatic steatosis without or with moderate inflammation and non-alcoholic steatohepatitis (NASH), characterized by necroinflammation and a more rapid progression of fibrosis. It is the primary pathological basis for hepatocellular carcinoma. With its prevalence escalating annually, NAFLD has emerged as a global health epidemic, presenting a significant hazard to public health worldwide. Existing studies have shown that physical activity and exercise training have a positive effect on NAFLD. However, the extent to which exercise improves NAFLD depends on the type, intensity, and duration. Therefore, the type of exercise that has the best effect on improving NAFLD remains to be explored. To date, the most valuable discussions involve aerobic and anaerobic exercise. Exercise intervenes in the pathological process of NAFLD by regulating physiological changes in cells through multiple signaling pathways. The review aims to summarize the signaling pathways affected by two different exercise types associated with the onset and progression of NAFLD. It provides a new basis for improving and managing NAFLD in clinical practice.
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Affiliation(s)
- F Qi
- Chongqing College of International Business and Economics, Southwest University, Chongqing, China, College of Physical Education, Southwest University, Chongqing, China.
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49
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Fougerat A, Bruse J, Polizzi A, Montagner A, Guillou H, Wahli W. Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting. Prog Lipid Res 2024; 96:101303. [PMID: 39521352 DOI: 10.1016/j.plipres.2024.101303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/18/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Peroxisome proliferator-activated receptors (PPARs) constitute a small family of three nuclear receptors that act as lipid sensors, and thereby regulate the transcription of genes having key roles in hepatic and whole-body energy homeostasis, and in other processes (e.g., inflammation), which have far-reaching health consequences. Peroxisome proliferator-activated receptor isotype α (PPARα) is expressed in oxidative tissues, particularly in the liver, carrying out critical functions during the adaptive fasting response. Advanced omics technologies have provided insight into the vast complexity of the regulation of PPAR expression and activity, as well as their downstream effects on the physiology of the liver and its associated metabolic organs. Here, we provide an overview of the gene regulatory networks controlled by PPARα in the liver in response to fasting. We discuss impacts on liver metabolism, the systemic repercussions and benefits of PPARα-regulated ketogenesis and production of fibroblast growth factor 21 (FGF21), a fasting- and stress-inducible metabolic hormone. We also highlight current challenges in using novel methods to further improve our knowledge of PPARα in health and disease.
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Affiliation(s)
- Anne Fougerat
- Toxalim (Research Centre in Toxicology), INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, France.
| | - Justine Bruse
- Toxalim (Research Centre in Toxicology), INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Centre in Toxicology), INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, France
| | - Alexandra Montagner
- Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM UMR1297, Toulouse III University, University Paul Sabatier (UPS), Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Centre in Toxicology), INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, France
| | - Walter Wahli
- Toxalim (Research Centre in Toxicology), INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, France; Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
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50
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Wang S, Xu B, Liang J, Feng Y, Han P, Shen J, Li X, Zheng M, Zhang T, Zhang C, Mi P, Zhang Y, Liu Z, Li S, Yuan D. Spatial Transcriptomic Study Reveals Heterogeneous Metabolic Adaptation and a Role of Pericentral PPARα/CAR/Ces2a Axis During Fasting in Mouse Liver. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405240. [PMID: 39234807 PMCID: PMC11538668 DOI: 10.1002/advs.202405240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/13/2024] [Indexed: 09/06/2024]
Abstract
Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal-spatial gene cascades and how liver zonation-both expression levels and patterns-adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances.
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Affiliation(s)
- Shiguan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
- Department of Clinical LaboratoryQilu Hospital of Shandong UniversityJinan250012China
| | - Bowen Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
- Advanced Medical Research InstituteShandong UniversityJinan250012China
| | - Jinyuan Liang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
| | - Yawei Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
| | - Penghu Han
- Advanced Medical Research InstituteShandong UniversityJinan250012China
| | - Jing Shen
- Advanced Medical Research InstituteShandong UniversityJinan250012China
| | - Xinying Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
| | - Mengqi Zheng
- Advanced Medical Research InstituteShandong UniversityJinan250012China
| | - Tingguo Zhang
- Institute of Pathology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinanShandong250012China
| | - Cuijuan Zhang
- Institute of Pathology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinanShandong250012China
| | - Ping Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
| | - Yi Zhang
- Department of Clinical LaboratoryQilu Hospital of Shandong UniversityJinan250012China
| | - Zhiping Liu
- Department of Biomedical Engineering, School of Control Science and EngineeringShandong UniversityJinanShandong250061China
| | - Shiyang Li
- Advanced Medical Research InstituteShandong UniversityJinan250012China
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of MedicineShandong UniversityJinan250012China
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