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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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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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Sepehri S, De Win D, Heymans A, Van Goethem F, Rodrigues RM, Rogiers V, Vanhaecke T. Next generation risk assessment of hair dye HC yellow no. 13: Ensuring protection from liver steatogenic effects. Regul Toxicol Pharmacol 2025; 159:105794. [PMID: 40024558 DOI: 10.1016/j.yrtph.2025.105794] [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: 10/09/2024] [Revised: 02/17/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
This study employs animal-free Next Generation Risk Assessment (NGRA) principles to evaluate the safety of repeated dermal exposure to 2.5% (w/w) HC Yellow No. 13 (HCY13) hair dye. As multiple in silico tools consistently flagged hepatotoxic potential, likely due to HCY13's trifluoromethyl group, which is known to interfere with hepatic lipid metabolism, liver steatosis was chosen as the primary mode of action for evaluation. AOP-guided in vitro tests were conducted, exposing human stem cell-derived hepatic cells to varying HCY13 concentrations over 72 h. The expression of 11 lipid metabolism-related marker genes (AHR, PPARA, LXRA, APOB, ACOX1, CPT1A, FASN, SCD1, DGAT2, CD36, and PPARG) and triglyceride accumulation, a phenotypic hallmark of steatosis, were measured. PROAST software was used to calculate in vitro Points of Departure (PoDNAM) for each biomarker. Using GastroPlus 9.9, physiologically-based pharmacokinetic (PBPK) models estimated internal liver concentrations (Cmax liver) of HCY13, ranging from 4 to 20 pM. All PoDNAM values significantly exceeded the predicted Cmax liver, indicating that HCY13 at 2.5% (w/w) is unlikely to induce liver steatosis under the assumed conditions. This research demonstrates the utility of NGRA, integrating AOP-based in vitro assays and computational models to protect human health and support regulatory decision-making without animal testing.
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Affiliation(s)
- Sara Sepehri
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Dinja De Win
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Anja Heymans
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Freddy Van Goethem
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Vera Rogiers
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
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Heldens A, Casteleyn C, Onghena L, Antwi M, Neyt S, Descamps B, Vanhove C, Verhelst X, Raevens S, Van Vlierberghe H, Devisscher L, De Bruyne R, Junien JL, Wettstein G, Geerts A, Lefere S. The pan-PPAR agonist lanifibranor reduces portal pressure independent of fibrosis reduction through the splanchnic vasculature. Biomed Pharmacother 2025; 183:117826. [PMID: 39805191 DOI: 10.1016/j.biopha.2025.117826] [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: 11/13/2024] [Revised: 12/22/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025] Open
Abstract
Portal hypertension (PH) can cause severe complications in patients with advanced chronic liver disease (aCLD). The pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor reduces portal pressure in preclinical models of aCLD. Since the effect on PH might be secondary to fibrosis improvement, we investigated the effect of lanifibranor on PH, hepatic and splanchnic angiogenesis in mouse models of fibrotic and prehepatic non-fibrotic PH. Mice with fibrotic PH (common bile duct ligation; CBDL) and prehepatic PH (partial portal vein ligation; PPVL) received daily lanifibranor/vehicle for 14 or 7 days, respectively. Hemodynamics, serum, hepatic and mesenteric histology, and hepatic, mesenteric and liver sinusoidal endothelial cells (LSEC) gene expression levels were analyzed. Vascular corrosion casts of the venous mesenteric and hepatic vasculature were analyzed using scanning electron microscopy and µCT. Portal pressure was increased in CBDL mice. Lanifibranor treatment demonstrated a dose-dependent trend towards decreasing the elevated portal pressure, and reduced fibrosis. Hepatic mRNA levels of inflammatory, fibrotic and angiogenic markers were significantly downregulated in lanifibranor-treated CBDL mice. LSEC dysfunction was improved by lanifibranor. Compared to CBDL mice, portal pressure was more extensively elevated in PPVL mice, which was significantly reduced by lanifibranor. Superior mesenteric artery blood flow, which was increased in vehicle-treated PPVL mice, tended to decrease by lanifibranor. The expansion of the mesenteric vasculature and mesenteric protein level of angiogenetic markers in PPVL mice were reduced after lanifibranor. In conclusion, lanifibranor improves PH, independently from fibrosis reduction, potentially through reducing the venous mesenteric vasculature expansion and intrahepatic angiogenesis, and ameliorating LSEC function.
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Affiliation(s)
- Anneleen Heldens
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Christophe Casteleyn
- Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Ghent University, Ghent, Belgium
| | - Louis Onghena
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Department of Human Structure and Repair, Department of Gastrointestinal Surgery, Ghent University, Ghent, Belgium
| | - Milton Antwi
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology unit, Ghent University, Ghent, Belgium; Translational Nuclear Receptor Research, Department of Biomolecular Medicine, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Sara Neyt
- Department of Electronics and Information Systems, IBiTech-MEDISIP, Ghent University, Ghent, Belgium
| | - Benedicte Descamps
- Department of Electronics and Information Systems, IBiTech-MEDISIP, Ghent University, Ghent, Belgium
| | - Christian Vanhove
- Department of Electronics and Information Systems, IBiTech-MEDISIP, Ghent University, Ghent, Belgium
| | - Xavier Verhelst
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Sarah Raevens
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Lindsey Devisscher
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium; Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology unit, Ghent University, Ghent, Belgium
| | - Ruth De Bruyne
- Department of Internal Medicine and Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University, Ghent, Belgium
| | | | | | - Anja Geerts
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Sander Lefere
- Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
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Jin L, Zhu W, Hu X, Ye L, Lou S, Zhang Q, Wang M, Ye B, Min J, Wang Y, Huang L, Luo W, Liang G. USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice. Cell Death Differ 2025:10.1038/s41418-025-01444-4. [PMID: 39827322 DOI: 10.1038/s41418-025-01444-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 12/08/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25's protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα's lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.
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Affiliation(s)
- Leiming Jin
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Weiwei Zhu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiang Hu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Lin Ye
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shuaijie Lou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Qianhui Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Minxiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Bozhi Ye
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Julian Min
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Yi Wang
- The Affiliated Xiangshan Hospital, Wenzhou Medical University, Xiangshan, Zhejiang, 315799, China
- School of Pharmaceutical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, 310000, China
| | - Lijiang Huang
- The Affiliated Xiangshan Hospital, Wenzhou Medical University, Xiangshan, Zhejiang, 315799, China.
| | - Wu Luo
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Guang Liang
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China.
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Li Q, Sheng J, Baruscotti M, Liu Z, Wang Y, Zhao L. Identification of Senkyunolide I as a novel modulator of hepatic steatosis and PPARα signaling in zebrafish and hamster models. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118743. [PMID: 39209000 DOI: 10.1016/j.jep.2024.118743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/19/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.
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Affiliation(s)
- Qingquan Li
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jian Sheng
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mirko Baruscotti
- Department of Biosciences, University of Milano, Milan, 1-20133, Italy
| | - Zhenjie Liu
- Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310020, China
| | - Lu Zhao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University Medical School, Hangzhou, 310003, China; State Key Laboratory of Chinese Medicine Modernization, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Katsarou A, Tsioulos G, Kassi E, Chatzigeorgiou A. Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease. Hormones (Athens) 2024; 23:621-636. [PMID: 39112786 DOI: 10.1007/s42000-024-00588-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/17/2024] [Indexed: 10/29/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.
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Affiliation(s)
- Angeliki Katsarou
- 251 Hellenic Airforce General Hospital, 1 P.Kanellopoulou Str, Athens, 11525, Greece.
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece.
| | - Georgios Tsioulos
- 4th Department of Internal Medicine, Medical School, University General Hospital Attikon, National and Kapodistrian University of Athens, 1 Rimini Str, Athens, 12462, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece
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Iwaki M, Kobayashi T, Nogami A, Ogawa Y, Imajo K, Sakai E, Nakada Y, Koyama S, Kurihashi T, Oza N, Kohira T, Okada M, Yamaguchi Y, Iwane S, Kageyama F, Sasada Y, Matsushita M, Tadauchi A, Murohisa G, Nagasawa M, Sato S, Maeda K, Furuta K, Shigefuku R, Seko Y, Tobita H, Kawata K, Kawanaka M, Sugihara T, Tamaki N, Iwasa M, Kawaguchi T, Itoh Y, Kawaguchi A, Takahashi H, Nakajima A, Yoneda M. Pemafibrate for treating MASLD complicated by hypertriglyceridaemia: a multicentre, open-label, randomised controlled trial study protocol. BMJ Open 2024; 14:e088862. [PMID: 39581726 PMCID: PMC11590823 DOI: 10.1136/bmjopen-2024-088862] [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: 05/16/2024] [Accepted: 10/25/2024] [Indexed: 11/26/2024] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH. METHODS AND ANALYSIS This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20-80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities. ETHICS AND DISSEMINATION Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. Participants wishing to understand the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280). PROTOCOL VERSION V.1.9, 23 November 2023.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, National Hospital Organisation Yokohama Medical Center, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology, Shin Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan
| | - Eiji Sakai
- Department of Gastroenterology, Yokohama Sakae Kyosai Hospital, Yokohama, Japan
| | - Yoshinobu Nakada
- Department of Internal Medicine, Shonan Hospital, Yokosuka, Kanagawa, Japan
| | - Satoshi Koyama
- Department of Internal Medicine, NamikiKoiso-Medical Clinic, Yokohama, Japan
| | - Takeo Kurihashi
- Department of Internal Medicine, Kanagawa Dental University Yokohama Clinic, Yokohama, Japan
| | - Noriko Oza
- Department of Hepato-Biliary-Pancreatology, Saga Prefecture Medical Center Koseikan, Saga, Saga, Japan
| | | | - Michiaki Okada
- Department of Internal Medicine, Karatsu Red Cross Hospital, Karatsu, Japan
| | - Yuki Yamaguchi
- Department of Internal Medicine, Masuda Red Cross Hospital, Masuda, Japan
| | - Shinji Iwane
- Department of Internal Medicine, Fujioka Hospital, Saga, Japan
| | - Fujito Kageyama
- Department of Gastroenterology and Hepatology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan
| | - Yuzo Sasada
- Division of Hepatology, Iwata City Hospital, Iwata, Japan
| | | | - Akimitsu Tadauchi
- Department of Gastroenterology, Seirei Mikatahara Byoin, Hamamatsu, Shizuoka, Japan
| | - Gou Murohisa
- Department of Gastroenterology, Seirei Hamamatsu Byoin, Hamamatsu, Shizuoka, Japan
| | - Masamichi Nagasawa
- Department of Gastroenterology, Seirei Hamamatsu Byoin, Hamamatsu, Shizuoka, Japan
| | - Shuichi Sato
- Department of Internal Medicine, Izumo City General Medical Center, Izumo, Japan
| | - Kazuhisa Maeda
- Department of Internal Medicine, Kitasenri Maeda Clinic, Suita, Japan
| | - Koichiro Furuta
- Department of Gastroenterology, National Hospital Organization Hamada Medical Center, Hamada, Japan
| | - Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine Faculty of Medicine, Tsu, Mie, Japan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, Shimane, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, Kawasaki Medical Center, Kawasaki Medical School, Kurashiki, Japan
| | - Takaaki Sugihara
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine Graduate School of Medicine, Yonago, Tottori, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine Faculty of Medicine, Tsu, Mie, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Liver Center, Saga University Hospital, Saga, Saga, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan
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9
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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10
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Vu HT, Nguyen VD, Ikenaga H, Matsubara T. Application of PPAR Ligands and Nanoparticle Technology in Metabolic Steatohepatitis Treatment. Biomedicines 2024; 12:1876. [PMID: 39200340 PMCID: PMC11351628 DOI: 10.3390/biomedicines12081876] [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: 07/29/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is a major disease worldwide whose effective treatment is challenging. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and function as ligand-activated transcription factors. To date, three distinct subtypes of PPARs have been characterized: PPARα, PPARβ/δ, and PPARγ. PPARα and PPARγ are crucial regulators of lipid metabolism that modulate the transcription of genes involved in fatty acid (FA), bile acid, and cholesterol metabolism. Many PPAR agonists, including natural (FAs, eicosanoids, and phospholipids) and synthetic (fibrate, thiazolidinedione, glitazar, and elafibranor) agonists, have been developed. Furthermore, recent advancements in nanoparticles (NPs) have led to the development of new strategies for MASLD/MASH therapy. This review discusses the applications of specific cell-targeted NPs and highlights the potential of PPARα- and PPARγ-targeted NP drug delivery systems for MASLD/MASH treatment.
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Affiliation(s)
- Hung Thai Vu
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Vien Duc Nguyen
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Osaka, Japan; (H.T.V.); (V.D.N.)
- Research Institute for Light-induced Acceleration System (RILACS), Osaka Metropolitan University, Sakai 599-8570, Osaka, Japan
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11
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Fan S, Gao Y, Zhao P, Xie G, Zhou Y, Yang X, Li X, Zhang S, Gonzalez FJ, Qu A, Huang M, Bi H. Fenofibrate-promoted hepatomegaly and liver regeneration are PPAR α-dependent and partially related to the YAP pathway. Acta Pharm Sin B 2024; 14:2992-3008. [PMID: 39027236 PMCID: PMC11252459 DOI: 10.1016/j.apsb.2024.03.030] [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: 11/20/2023] [Revised: 01/26/2024] [Accepted: 03/03/2024] [Indexed: 07/20/2024] Open
Abstract
Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP-TEAD complex. Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
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Affiliation(s)
- Shicheng Fan
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Pengfei Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Guomin Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yanying Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xiao Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
| | - Xuan Li
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shuaishuai Zhang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Huichang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
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12
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Pramanik S, Pal P, Ray S. Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies. World J Methodol 2024; 14:91319. [PMID: 38983664 PMCID: PMC11229880 DOI: 10.5662/wjm.v14.i2.91319] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/20/2024] [Accepted: 02/27/2024] [Indexed: 06/13/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.
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Affiliation(s)
- Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospital, Siliguri 734010, West Bengal, India
| | - Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Sayantan Ray
- Department of Endocrinology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar 751019, Odisha, India
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13
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Fang Z, Shen G, Wang Y, Hong F, Tang X, Zeng Y, Zhang T, Liu H, Li Y, Wang J, Zhang J, Gao A, Qi W, Yang X, Zhou T, Gao G. Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease. Signal Transduct Target Ther 2024; 9:66. [PMID: 38472195 PMCID: PMC10933339 DOI: 10.1038/s41392-024-01781-9] [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: 09/16/2023] [Revised: 02/14/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.
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Affiliation(s)
- Zhenzhen Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Gang Shen
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yina Wang
- Department of VIP Medical Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Fuyan Hong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiumei Tang
- Physical Examination Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yongcheng Zeng
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ting Zhang
- Department of Clinical Laboratory, Guangzhou First People's Hospital, Guangzhou, 510080, China
| | - Huanyi Liu
- Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yanmei Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jinhong Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jing Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Anton Gao
- Department of Health Sciences, College of Health Solutions, Arizona State University, Tempe, USA
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xia Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Ti Zhou
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Diabetology, Guangzhou, 510080, China.
| | - Guoquan Gao
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
- Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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14
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Zhu B, Wu H, Li KS, Eisa-Beygi S, Singh B, Bielenberg DR, Huang W, Chen H. Two sides of the same coin: Non-alcoholic fatty liver disease and atherosclerosis. Vascul Pharmacol 2024; 154:107249. [PMID: 38070759 DOI: 10.1016/j.vph.2023.107249] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/20/2023] [Accepted: 11/25/2023] [Indexed: 02/03/2024]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis remain high, which is primarily due to widespread adoption of a western diet and sedentary lifestyle. NAFLD, together with advanced forms of this disease such as non-alcoholic steatohepatitis (NASH) and cirrhosis, are closely associated with atherosclerotic-cardiovascular disease (ASCVD). In this review, we discussed the association between NAFLD and atherosclerosis and expounded on the common molecular biomarkers underpinning the pathogenesis of both NAFLD and atherosclerosis. Furthermore, we have summarized the mode of function and potential clinical utility of existing drugs in the context of these diseases.
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Affiliation(s)
- Bo Zhu
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Hao Wu
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Kathryn S Li
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Shahram Eisa-Beygi
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Bandana Singh
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Diane R Bielenberg
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolic Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, United States of America
| | - Hong Chen
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States of America.
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15
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Changizi Z, Kajbaf F, Moslehi A. An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases. J Clin Transl Hepatol 2023; 11:1542-1552. [PMID: 38161499 PMCID: PMC10752810 DOI: 10.14218/jcth.2023.00334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/17/2023] [Accepted: 10/09/2023] [Indexed: 01/03/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.
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Affiliation(s)
- Zahra Changizi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Forough Kajbaf
- Veterinary Department, Faculty of Agriculture, Islamic Azad University, Shoushtar Branch, Shoushtar, Iran
| | - Azam Moslehi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
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16
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Anwar SD, Foster C, Ashraf A. Lipid Disorders and Metabolic-Associated Fatty Liver Disease. Endocrinol Metab Clin North Am 2023; 52:445-457. [PMID: 37495336 DOI: 10.1016/j.ecl.2023.01.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
Dyslipidemia has been linked metabolic-associated fatty liver disease (MAFLD). Several genes and transcription factors involved in lipid metabolism can increase susceptibility to MAFLD. Multiple parallel 'hits' have been proposed for developing hepatic steatosis, NASH, and MAFLD, including insulin resistance and subsequent free fatty acid excess, de novo lipogenesis, and excessive hepatic triglyceride and cholesterol deposition in the liver. This lead to defective beta-oxidation in the mitochondria and VLDL export and increased inflammation. Given the significant cardiovascular risk, dyslipidemia associated with MAFLD should be managed by lifestyle changes and lipid-lowering agents such as statins, fenofibrate, and omega-3 fatty acids, with judicious use of insulin-sensitizing agents, and adequate control of dysglycemia.
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Affiliation(s)
- Shima Dowla Anwar
- Department of Pediatrics, Boston Children Hospital, Harvard Medical School, Boston, MA, USA
| | - Christy Foster
- University of Alabama at Birmingham, 1601, 4th Avenue South, CPP M 30, Birmingham, AL 35233, USA
| | - Ambika Ashraf
- University of Alabama at Birmingham, 1601, 4th Avenue South, CPP M 30, Birmingham, AL 35233, USA.
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17
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Vitulo M, Gnodi E, Rosini G, Meneveri R, Giovannoni R, Barisani D. Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD. Int J Mol Sci 2023; 24:12748. [PMID: 37628929 PMCID: PMC10454602 DOI: 10.3390/ijms241612748] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.
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Affiliation(s)
- Manuela Vitulo
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Elisa Gnodi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Giulia Rosini
- Department of Biology, University of Pisa, 56021 Pisa, Italy; (G.R.); (R.G.)
| | - Raffaella Meneveri
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Roberto Giovannoni
- Department of Biology, University of Pisa, 56021 Pisa, Italy; (G.R.); (R.G.)
| | - Donatella Barisani
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
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18
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Gagnon E, Manikpurage HD, Mitchell PL, Girard A, Gobeil É, Bourgault J, Bégin F, Marette A, Thériault S, Arsenault BJ. Large-scale metabolomic profiling and incident non-alcoholic fatty liver disease. iScience 2023; 26:107127. [PMID: 37456853 PMCID: PMC10339047 DOI: 10.1016/j.isci.2023.107127] [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: 04/14/2023] [Revised: 05/11/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032 UK Biobank participants. We identified several metabolic factors associated with NAFLD risk in observational and MR analyses including triglyceride-rich and high-density lipoprotein particles composition, as well as the ratio of polyunsaturated fatty acids to total fatty acids. This study, is one of the largest to investigate incident NAFLD, provides concordant observational and genetic evidence that therapies aimed at reducing circulating triglycerides and increasing large HDL particles, as well as interventions aimed at increasing polyunsaturated fatty acid content may warrant further investigation into NAFLD prevention and treatment.
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Affiliation(s)
- Eloi Gagnon
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Hasanga D. Manikpurage
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Patricia L. Mitchell
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Arnaud Girard
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Émilie Gobeil
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Jérôme Bourgault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - Frédéric Bégin
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
| | - André Marette
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Québec (QC), Canada
| | - Sébastien Thériault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec (QC), Canada
| | - Benoit J. Arsenault
- Centre de Recherche de L’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec (QC), Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Québec (QC), Canada
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19
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Wang X, Luo J, Lu Z, Fang S, Sun M, Luo W, Shen J, Liu A, Ye H. Therapeutic effect of fenofibrate for non-alcoholic steatohepatitis in mouse models is dependent on regime design. Front Pharmacol 2023; 14:1190458. [PMID: 37251331 PMCID: PMC10213340 DOI: 10.3389/fphar.2023.1190458] [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: 03/20/2023] [Accepted: 05/03/2023] [Indexed: 05/31/2023] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases. In most cases, NAFLD progresses from benign steatosis to steatohepatitis (NASH), and then to cirrhosis. No treatment is currently approved for NAFLD/NASH in the clinic. Fenofibrate (FENO) has been clinically used to treat dyslipidemia for more than a half century, but its effects on NASH are not established. FENO's half-life is quite different between rodent and human. The aim of this study was to investigate the potential of pharmacokinetic-based FENO regime for NASH treatment and the underlying mechanisms. Methods: Two typical mouse NASH models, methionine-choline deficient (MCD) diet-fed mice and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, were used. MCD model was designed as therapeutic evaluation in experiment 1 and CDAHFD model was designed as preventive in experiment 2. Three doses of FENO (5, 25, 125 mg/kg), two times a day (BID), were administered to the above models. Serum markers of liver injury, cholestasis, and the histology of liver tissues were investigated. Normal mice were used as a model in experiment 3 for toxicity evaluation, Quantitative-PCR and Western Blot assays were used to investigate the inflammatory responses, bile acid synthesis as well as lipid catabolism. Results: Mice on the MCD and CDAHFD diets developed steatohepatitis as expected. Treatment with FENO (25 mg/kg·BID) significantly decreased hepatic steatosis, inflammation and fibrosis in both therapeutic and preventive models. In the MCD model, the therapeutic action of FENO (25 mg/kg·BID) and 125 mg/kg·BID on histopathology and the expression of inflammatory cytokines were comparable. In reducing macrophage infiltration and bile acid load, FENO (25 mg/kg·BID) was superior to 125 mg/kg·BID. In all the aspects mentioned above, FENO (25 mg/kg·BID) was the best among the 3 doses in the CDAHFD model. In a third experiment, the effects of FENO (25 mg/kg·BID) and 125 mg/kg·BID on lipid catabolism were comparable, but 125 mg/kg·BID increased the expression of inflammatory factors and bile acid load. In both models, FENO (5 mg/kg·BID) showed little effect in hepatic steatosis and inflammation, neither the adverse effects. FENO (125 mg/kg·BID) aggravated liver inflammation, increased bile acid synthesis, and promoted the potential of liver proliferation. In toxicity risk assay, FENO (25 mg/kg·BID) treatment showed low potential to trigger bile acid synthesis, inflammation and hepatocyte proliferation. Conclusion: A new regime, FENO (25 mg/kg·BID) is potentially a therapeutic strategy for the NASH treatment. Translational medicine is warranted to prove its effectiveness in the clinic.
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Affiliation(s)
- Xinxue Wang
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jia Luo
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Zhuoheng Lu
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Shenzhe Fang
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Mengxia Sun
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Wenjing Luo
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jianwei Shen
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Aiming Liu
- Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, China
| | - Hua Ye
- Department of Gastroenterology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
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Noureddin M, Abdelmalek MF. Current Treatment Options, Including Diet, Exercise, and Medications: The Impact on Histology. Clin Liver Dis 2023; 27:397-412. [PMID: 37024215 DOI: 10.1016/j.cld.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Paralleling the rise in obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, may progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Despite its public health treat, no approved pharmacotherapies for NAFLD/NASH currently exist. Although the armamentarium of therapies for NASH is limited, current treatment options include life-style modification and the use of medications to treat metabolic comorbidities. This review addresses current approaches to the treatment of NAFLD/NASH, including the impact of diet, exercise, and available pharmacotherapies on the histologic features of liver injury.
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Affiliation(s)
- Mazen Noureddin
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA; Houston Research Institute and Houston Liver Institute, Houston, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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21
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Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023; 77:1797-1835. [PMID: 36727674 PMCID: PMC10735173 DOI: 10.1097/hep.0000000000000323] [Citation(s) in RCA: 924] [Impact Index Per Article: 462.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 02/03/2023]
Affiliation(s)
- Mary E. Rinella
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | | | | | | | - Stephen Caldwell
- School of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Diana Barb
- University of Florida College of Medicine, Gainesville, Florida, USA
| | | | - Rohit Loomba
- University of California, San Diego, San Diego, California, USA
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22
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Pydyn N, Kadluczka J, Major P, Hutsch T, Belamri K, Malczak P, Radkowiak D, Budzynski A, Miekus K, Jura J, Kotlinowski J. Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium. Hepatol Commun 2023; 7:e0008. [PMID: 36809310 PMCID: PMC9949814 DOI: 10.1097/hc9.0000000000000008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/20/2022] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND AND AIMS NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. METHODS In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating β-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). CONCLUSION We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.
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Affiliation(s)
- Natalia Pydyn
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Justyna Kadluczka
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
- Department of Neuropsychopharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
| | - Piotr Major
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | - Tomasz Hutsch
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
- Veterinary Diagnostic Laboratory ALAB Bioscience, Warsaw, Poland
| | - Kinga Belamri
- Veterinary Diagnostic Laboratory ALAB Bioscience, Warsaw, Poland
| | - Piotr Malczak
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | - Dorota Radkowiak
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | - Andrzej Budzynski
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland
| | - Katarzyna Miekus
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jolanta Jura
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jerzy Kotlinowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
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23
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Finney AC, Das S, Kumar D, McKinney MP, Cai B, Yurdagul A, Rom O. The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1116861. [PMID: 37200978 PMCID: PMC10185914 DOI: 10.3389/fcvm.2023.1116861] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/23/2023] [Indexed: 05/20/2023] Open
Abstract
Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.
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Affiliation(s)
- Alexandra C. Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Sandeep Das
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Dhananjay Kumar
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - M. Peyton McKinney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Bishuang Cai
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, United States
| | - Arif Yurdagul
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
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24
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PPARα in the Epigenetic Driver Seat of NAFLD: New Therapeutic Opportunities for Epigenetic Drugs? Biomedicines 2022; 10:biomedicines10123041. [PMID: 36551797 PMCID: PMC9775974 DOI: 10.3390/biomedicines10123041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/11/2022] [Accepted: 11/16/2022] [Indexed: 11/27/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic and the most common cause of chronic liver disease worldwide. It consists of a spectrum of liver disorders ranging from simple steatosis to NASH which predisposes patients to further fibrosis, cirrhosis and even hepatocarcinoma. Despite much research, an approved treatment is still lacking. Finding new therapeutic targets has therefore been a main priority. Known as a main regulator of the lipid metabolism and highly expressed in the liver, the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) has been identified as an attractive therapeutic target. Since its expression is silenced by DNA hypermethylation in NAFLD patients, many research strategies have aimed to restore the expression of PPARα and its target genes involved in lipid metabolism. Although previously tested PPARα agonists did not ameliorate the disease, current research has shown that PPARα also interacts and regulates epigenetic DNMT1, JMJD3, TET and SIRT1 enzymes. Moreover, there is a growing body of evidence suggesting the orchestrating role of epigenetics in the development and progression of NAFLD. Therefore, current therapeutic strategies are shifting more towards epigenetic drugs. This review provides a concise overview of the epigenetic regulation of NAFLD with a focus on PPARα regulation and highlights recently identified epigenetic interaction partners of PPARα.
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25
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Fu Y, Zhou Y, Shen L, Li X, Zhang H, Cui Y, Zhang K, Li W, Chen WD, Zhao S, Li Y, Ye W. Diagnostic and therapeutic strategies for non-alcoholic fatty liver disease. Front Pharmacol 2022; 13:973366. [PMID: 36408234 PMCID: PMC9666875 DOI: 10.3389/fphar.2022.973366] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 10/18/2022] [Indexed: 11/07/2022] Open
Abstract
The global incidence rate of non-alcoholic fatty liver disease (NAFLD) is approximately 25%. With the global increase in obesity and its associated metabolic syndromes, NAFLD has become an important cause of chronic liver disease in many countries. Despite recent advances in pathogenesis, diagnosis, and therapeutics, there are still challenges in its treatment. In this review, we briefly describe diagnostic methods, therapeutic targets, and drugs related to NAFLD. In particular, we focus on evaluating carbohydrate and lipid metabolism, lipotoxicity, cell death, inflammation, and fibrosis as potential therapeutic targets for NAFLD. We also summarized the clinical research progress in terms of drug development and combination therapy, thereby providing references for NAFLD drug development.
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Affiliation(s)
- Yajie Fu
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Yanzhi Zhou
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Linhu Shen
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Xuewen Li
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Haorui Zhang
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Yeqi Cui
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Ke Zhang
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Weiguo Li
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
| | - Wei-dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
| | - Shizhen Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
- *Correspondence: Shizhen Zhao, ; Yunfu Li, ; Wenling Ye,
| | - Yunfu Li
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
- *Correspondence: Shizhen Zhao, ; Yunfu Li, ; Wenling Ye,
| | - Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, The People’s Hospital of Hebi, Henan University, Kaifeng, China
- *Correspondence: Shizhen Zhao, ; Yunfu Li, ; Wenling Ye,
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Handelman SK, Puentes YM, Kuppa A, Chen Y, Du X, Feitosa MF, Palmer ND, Speliotes EK. Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids. Hepatol Commun 2022; 6:3120-3131. [PMID: 36098472 PMCID: PMC9592792 DOI: 10.1002/hep4.2066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 02/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low-density lipoprotein cholesterol (LDL), and reduced high-density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome-wide association studies (GWAS)-ranked genes and gene-set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European-ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African-ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance-associated protein 2)], ABCG5, ABCG8 [ATP-binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid-binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone-mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.
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Affiliation(s)
- Samuel K. Handelman
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Yindra M. Puentes
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Annapurna Kuppa
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Yanhua Chen
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Xiaomeng Du
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Mary F. Feitosa
- Division of Statistical Genomics, Department of GeneticsWashington UniversitySt. LouisMissouriUSA
| | - Nicholette D. Palmer
- Department of BiochemistryWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Elizabeth K. Speliotes
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
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Garbuzenko DV. Current strategies for targeted therapy of liver fibrosis. BULLETIN OF SIBERIAN MEDICINE 2022. [DOI: 10.20538/1682-0363-2022-3-154-165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Liver fibrosis (LF) is an unfavorable event in the natural course of chronic liver diseases (CLD), therefore, early implementation and widespread use of antifibrotic therapy methods is a pressing issue in hepatology. The aim of the review was to describe current approaches to targeted therapy of LF.PubMed database, Google Scholar search engine, Cochrane Database of Systematic Reviews, eLIBRARY.RU scientific electronic library, as well as reference lists of articles were used to search for scientific articles. The publications that corresponded to the aim of the study were selected for the period from 1998 to 2021 by the terms “liver fibrosis”, “pathogenesis”, and “treatment”. Inclusion criteria were restricted to targeted therapy of LF.Despite the growing evidence for reversibility of LF, there are currently no effective or clinically approved regimens for its specific therapy. However, taking into account the relevance of the issue, scientific research in this area is necessary. Multiple drugs with a good safety profile have been studied, which, though intended for other purposes, can have a positive effect on LF. In addition, a number of innovative approaches that differ from pharmacotherapy inspire optimism about finding a solution to this problem. It is obvious that studies focused on well-characterized groups of patients with confirmed histologic, elastography, clinical, and radiological parameters are required. This is a challenging task, since the key point will be stratification of risk based on ethnicity, etiology, and clinical status, and very large samples will be required for a reliable assessment. Nevertheless, the solution will increase efficiency of treatment for patients with CLD, improve their prognosis and quality of life, and significantly reduce the need for liver transplantation, a demand for which remains extremely high worldwide.
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Zhou S, You H, Qiu S, Yu D, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Biomed Pharmacother 2022; 154:113577. [PMID: 35988420 DOI: 10.1016/j.biopha.2022.113577] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is primarily caused by abnormal lipid metabolism and the accumulation of triglycerides in the liver. NAFLD is also associated with hepatic steatosis and nutritional and energy imbalances and is a chronic liver disease associated with a number of factors. Nuclear receptors play a key role in balancing energy and nutrient metabolism, and the peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR) regulate lipid metabolism genes, controlling hepatocyte lipid utilization and regulating bile acid (BA) synthesis and transport. They play an important role in lipid metabolism and BA homeostasis. At present, PPARα and FXR are the most promising targets for the treatment of NAFLD among nuclear receptors. This review focuses on the crosstalk mechanisms and transcriptional regulation of PPARα and FXR in the pathogenesis of NAFLD and summarizes PPARα and FXR drugs in clinical trials, laying a theoretical foundation for the targeted treatment of NAFLD and the development of novel therapeutic strategies.
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Affiliation(s)
- Shipeng Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Huimin You
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Shuting Qiu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Dawei Yu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Sommerauer C, Kutter C. Noncoding RNAs in liver physiology and metabolic diseases. Am J Physiol Cell Physiol 2022; 323:C1003-C1017. [PMID: 35968891 DOI: 10.1152/ajpcell.00232.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The liver holds central roles in detoxification, energy metabolism and whole-body homeostasis but can develop malignant phenotypes when being chronically overwhelmed with fatty acids and glucose. The global rise of metabolic-associated fatty liver disease (MAFLD) is already affecting a quarter of the global population. Pharmaceutical treatment options against different stages of MAFLD do not yet exist and several clinical trials against hepatic transcription factors and other proteins have failed. However, emerging roles of noncoding RNAs, including long (lncRNA) and short noncoding RNAs (sRNA), in various cellular processes pose exciting new avenues for treatment interventions. Actions of noncoding RNAs mostly rely on interactions with proteins, whereby the noncoding RNA fine-tunes protein function in a process termed riboregulation. The developmental stage-, disease stage- and cell type-specific nature of noncoding RNAs harbors enormous potential to precisely target certain cellular pathways in a spatio-temporally defined manner. Proteins interacting with RNAs can be categorized into canonical or non-canonical RNA binding proteins (RBPs) depending on the existence of classical RNA binding domains. Both, RNA- and RBP-centric methods have generated new knowledge of the RNA-RBP interface and added an additional regulatory layer. In this review, we summarize recent advances of how of RBP-lncRNA interactions and various sRNAs shape cellular physiology and the development of liver diseases such as MAFLD and hepatocellular carcinoma.
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Affiliation(s)
- Christian Sommerauer
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
| | - Claudia Kutter
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, grid.4714.6Karolinska Institute, Stockholm, Sweden
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30
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Qiu H, Song E, Hu Y, Li T, Ku KC, Wang C, Cheung BMY, Cheong LY, Wang Q, Wu X, Hoo RLC, Wang Y, Xu A. Hepatocyte-Secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARα/FGF21 Axis. Cell Mol Gastroenterol Hepatol 2022; 14:1003-1023. [PMID: 35931383 PMCID: PMC9490100 DOI: 10.1016/j.jcmgh.2022.07.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD. METHODS The clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin. RESULTS Serum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice. CONCLUSIONS Liver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.
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Affiliation(s)
- Han Qiu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Erfei Song
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yue Hu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tengfei Li
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kam Ching Ku
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Cunchuan Wang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bernard M Y Cheung
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lai Yee Cheong
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Qin Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiaoping Wu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Ruby L C Hoo
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Yong Wang
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, China.
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
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31
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Lian B, Cai L, Zhang Z, Lin F, Li Z, Zhang XK, Jiang F. The anti-inflammatory effect of Pien Tze Huang in non-alcoholic fatty liver disease. Biomed Pharmacother 2022; 151:113076. [PMID: 35550529 DOI: 10.1016/j.biopha.2022.113076] [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: 01/08/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease that may progress to nonalcoholic steatohepatitis (NASH), hepatic tissue fibrosis, liver cirrhosis, and hepatocellular carcinoma. In this study, we investigated the effects of Pien Tze Huang (PTH), a well-known traditional Chinese herbal formula with liver protective effect, in methionine-choline deficient diet (MCD)- and high-fat diet (HFD)-induced NASH mouse models. Our results showed that PTH could exert hepatoprotective effects by improving liver weight and steatosis and reducing the fibrosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) in both animal models. The effects of PTH was accompanied with the reduction of infiltrated macrophages, the inhibition of the expression of cytokines, and the induction of adiponectin expression. Mechanistically, we found that PTH could inhibit the activation of proinflammatory transcription factor nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor of κBα (IκBα). These results demonstrate that PTH can improve NAFLD largely due to its suppression of the NF-κB inflammatory pathway.
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Affiliation(s)
- Baohuan Lian
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.; NucMito Pharmaceuticals Co. Ltd., Xiamen, 361101, China
| | - Lijun Cai
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Zhaoqiang Zhang
- Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, China
| | - Fen Lin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Zongxi Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Xiao-Kun Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China..
| | - Fuquan Jiang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China..
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Liver Protective Effect of Fenofibrate in NASH/NAFLD Animal Models. PPAR Res 2022; 2022:5805398. [PMID: 35754743 PMCID: PMC9232374 DOI: 10.1155/2022/5805398] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/19/2022] [Accepted: 06/02/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is initiated by excessive fat buildup in the liver, affecting around 35% of the world population. Various circumstances contribute to the initiation and progression of NAFLD, and it encompasses a wide range of disorders, from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. Although several treatments have been proposed, there is no definitive cure for NAFLD. In recent decades, several medications related to other metabolic disorders have been evaluated in preclinical studies and in clinical trials due to the correlation of NAFLD with other metabolic diseases. Fenofibrate is a fibrate drug approved for dyslipidemia that could be used for modulation of hepatic fat accumulation, targeting peroxisome proliferator-activator receptors, and de novo lipogenesis. This drug offers potential therapeutic efficacy for NAFLD due to its capacity to decrease the accumulation of hepatic lipids, as well as its antioxidant, anti-inflammatory, and antifibrotic properties. To better elucidate the pathophysiological processes underlying NAFLD, as well as to test therapeutic agents/interventions, experimental animal models have been extensively used. In this article, we first reviewed experimental animal models that have been used to evaluate the protective effects of fenofibrate on NAFLD/NASH. Next, we investigated the impact of fenofibrate on the hepatic microcirculation in NAFLD and then summarized the beneficial effects of fenofibrate, as compared to other drugs, for the treatment of NAFLD. Lastly, we discuss possible adverse side effects of fenofibrate on the liver.
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PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH). BIOLOGY 2022; 11:biology11050792. [PMID: 35625520 PMCID: PMC9138523 DOI: 10.3390/biology11050792] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/31/2022]
Abstract
Simple Summary In the context of liver disease, one of the more growing public health problems is the transition from simple steatosis to non-alcoholic steatohepatitis. Profound metabolic dysregulations linked to inflammation and hepatic injury are features of non-alcoholic steatohepatitis. Since the peroxisomal-proliferator-activated receptor alpha has long been considered one of the key transcriptional factors in hepatic metabolism, its role in the pathogenesis of non-alcoholic steatohepatitis is discussed in this review. Abstract The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity and mortality. Therefore, an effort to understand the mechanisms underlying the pathogenesis of NASH is critical. Among the nuclear receptor transcription factors, peroxisome-proliferator-activated receptor alpha (PPARα) is highly expressed in the liver, where it works as a pivotal transcriptional regulator of the intermediary metabolism. In this context, PPARα’s function in regulating the lipid metabolism is essential for proper liver functioning. Here, we review metabolic liver genes under the control of PPARα and discuss how this aspect can impact the inflammatory condition and pathogenesis of NASH.
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Mahmoudi A, Jamialahmadi T, Johnston TP, Sahebkar A. Impact of fenofibrate on NAFLD/NASH: A genetic perspective. Drug Discov Today 2022; 27:2363-2372. [PMID: 35569762 DOI: 10.1016/j.drudis.2022.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/13/2022] [Accepted: 05/09/2022] [Indexed: 11/26/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), caused by an accumulation of fat deposits in hepatocytes, prevalently affects at least one-third of the world's population. The progression of this disorder can potentially include a spectrum of consecutive stages, specifically: steatosis, steatohepatitis and cirrhosis. Fenofibrate exhibits potential therapeutic efficacy for NAFLD owing to several properties, which include antioxidant, apoptotic, anti-inflammatory and antifibrotic activity. In the present review, we discuss the direct or indirect impact of fenofibrate on genes involved at various stages in the progression of NAFLD. Moreover, we have reviewed studies that compare fenofibrate with other drugs in treating NAFLD, as well as recent clinical trials, in an attempt to identify reliable scientific and clinical evidence concerning the therapeutic effects and benefits of fenofibrate on NAFLD. Teaser.
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Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH. Acta Pharmacol Sin 2022; 43:1141-1155. [PMID: 35105958 PMCID: PMC9061859 DOI: 10.1038/s41401-022-00864-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/09/2022] [Indexed: 12/13/2022]
Abstract
Mitochondrial biology and behavior are central to the physiology of liver. Multiple mitochondrial quality control mechanisms remodel mitochondrial homeostasis under physiological and pathological conditions. Mitochondrial dysfunction and damage induced by overnutrition lead to oxidative stress, inflammation, liver cell death, and collagen production, which advance hepatic steatosis to nonalcoholic steatohepatitis (NASH). Accumulating evidence suggests that specific interventions that target mitochondrial homeostasis, including energy metabolism, antioxidant effects, and mitochondrial quality control, have emerged as promising strategies for NASH treatment. However, clinical translation of these findings is challenging due to the complex and unclear mechanisms of mitochondrial homeostasis in the pathophysiology of NASH.
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Vecera R, Poruba M, Hüttl M, Malinska H, Oliyarnyk O, Markova I, Racova Z, Soukop J, Kazdova L. Beneficial Effect of Fenofibrate and Silymarin on Hepatic Steatosis and Gene Expression of Lipogenic and Cytochrome P450 Enzymes in Non-Obese Hereditary Hypertriglyceridemic Rats. Curr Issues Mol Biol 2022; 44:1889-1900. [PMID: 35678658 PMCID: PMC9164080 DOI: 10.3390/cimb44050129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/14/2022] [Accepted: 04/22/2022] [Indexed: 11/16/2022] Open
Abstract
The efficacy of fenofibrate in the treatment of hepatic steatosis has not been clearly demonstrated. In this study, we investigated the effects of fenofibrate and silymarin, administered as monotherapy and in combination to existing hepatic steatosis in a unique strain of hereditary hypertriglyceridemic rats (HHTg), a non-obese model of metabolic syndrome. HHTg rats were fed a standard diet without or with fenofibrate (100 mg/kg b.wt./day) or with silymarin (1%) or with a combination of fenofibrate with silymarin for four weeks. Fenofibrate alone and in combination with silymarin decreased serum and liver triglycerides and cholesterol and increased HDL cholesterol. These effects were associated with the decreased gene expression of enzymes involved in lipid synthesis and transport, while enzymes of lipid conversion were upregulated. The combination treatment had a beneficial effect on the gene expression of hepatic cytochrome P450 (CYP) enzymes. The expression of the CYP2E1 enzyme, which is source of hepatic reactive oxygen species, was reduced. In addition, fenofibrate-induced increased CYP4A1 expression was decreased, suggesting a reduction in the pro-inflammatory effects of fenofibrate. These results show high efficacy and mechanisms of action of the combination of fenofibrate with silymarin in treating hepatic steatosis and indicate the possibility of protection against disorders in which oxidative stress and inflammation are involved.
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Affiliation(s)
- Rostislav Vecera
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic; (R.V.); (Z.R.); (J.S.)
| | - Martin Poruba
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic; (R.V.); (Z.R.); (J.S.)
- Correspondence: ; Tel.: +420-585-632-556
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (H.M.); (O.O.); (I.M.); (L.K.)
| | - Hana Malinska
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (H.M.); (O.O.); (I.M.); (L.K.)
| | - Olena Oliyarnyk
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (H.M.); (O.O.); (I.M.); (L.K.)
| | - Irena Markova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (H.M.); (O.O.); (I.M.); (L.K.)
| | - Zuzana Racova
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic; (R.V.); (Z.R.); (J.S.)
| | - Jan Soukop
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77515 Olomouc, Czech Republic; (R.V.); (Z.R.); (J.S.)
| | - Ludmila Kazdova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (H.M.); (O.O.); (I.M.); (L.K.)
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Lange NF, Graf V, Caussy C, Dufour JF. PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients. Int J Mol Sci 2022; 23:ijms23084305. [PMID: 35457120 PMCID: PMC9028563 DOI: 10.3390/ijms23084305] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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Affiliation(s)
- Naomi F. Lange
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, 3012 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
| | - Vanessa Graf
- Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Jean-François Dufour
- Centre des Maladies Digestives, 1003 Lausanne, Switzerland
- Swiss NASH Foundation, 3011 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
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Chen YW, Diamante G, Ding J, Nghiem TX, Yang J, Ha SM, Cohn P, Arneson D, Blencowe M, Garcia J, Zaghari N, Patel P, Yang X. PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool. iScience 2022; 25:104052. [PMID: 35345455 PMCID: PMC8957031 DOI: 10.1016/j.isci.2022.104052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/29/2022] [Accepted: 03/08/2022] [Indexed: 12/29/2022] Open
Abstract
Drug development has been hampered by a high failure rate in clinical trials due to our incomplete understanding of drug functions across organs and species. Therefore, elucidating species- and tissue-specific drug functions can provide insights into therapeutic efficacy, potential adverse effects, and interspecies differences necessary for effective translational medicine. Here, we present PharmOmics, a drug knowledgebase and analytical tool that is hosted on an interactive web server. Using tissue- and species-specific transcriptome data from human, mouse, and rat curated from different databases, we implemented a gene-network-based approach for drug repositioning. We demonstrate the potential of PharmOmics to retrieve known therapeutic drugs and identify drugs with tissue toxicity using in silico performance assessment. We further validated predicted drugs for nonalcoholic fatty liver disease in mice. By combining tissue- and species-specific in vivo drug signatures with gene networks, PharmOmics serves as a complementary tool to support drug characterization and network-based medicine.
Development of PharmOmics, a platform for drug repositioning and toxicity prediction Contains >18000 species/tissue-specific gene signatures for 941 drugs and chemicals Benchmarked and validated network-based drug repositioning and toxicity prediction PharmOmics is freely accessible via an online web server to facilitate user access
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Affiliation(s)
- Yen-Wei Chen
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Ding
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Thien Xuan Nghiem
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jessica Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Sung-Min Ha
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Peter Cohn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Douglas Arneson
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
| | - Jennifer Garcia
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Nima Zaghari
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Paul Patel
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular Toxicology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Molecular, Cellular, & Integrative Physiology, Los Angeles, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Corresponding author
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Tzanaki I, Agouridis AP, Kostapanos MS. Is there a role of lipid-lowering therapies in the management of fatty liver disease? World J Hepatol 2022; 14:119-139. [PMID: 35126843 PMCID: PMC8790403 DOI: 10.4254/wjh.v14.i1.119] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/30/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.
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Affiliation(s)
- Ismini Tzanaki
- School of Medicine, European University Cyprus, Nicosia, Cyprus, Nicosia 2404, Cyprus
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus
| | - Michael S Kostapanos
- General Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge CB20QQ, United Kingdom
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2021:3654660. [PMID: 34988225 PMCID: PMC8720586 DOI: 10.1155/2021/3654660] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 12/14/2021] [Indexed: 01/30/2023]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. Methods We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. Results We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Conclusion Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.
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Liao X, Ma Q, Wu T, Shao C, Lin Y, Sun Y, Feng S, Wang W, Ye J, Zhong B. Lipid-Lowering Responses to Dyslipidemia Determine the Efficacy on Liver Enzymes in Metabolic Dysfunction-Associated Fatty Liver Disease with Hepatic Injuries: A Prospective Cohort Study. Diabetes Metab Syndr Obes 2022; 15:1173-1184. [PMID: 35464261 PMCID: PMC9030404 DOI: 10.2147/dmso.s356371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/29/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Effective treatment of dyslipidemia with lipid-lowering agents is pivotal in the management of metabolic-associated fatty liver disease (MAFLD) for preventing cardiovascular complications. We explored the associations between improvements in liver injuries indicated by changes in transaminases and a reduction in lipid levels in MAFLD patients with dyslipidemia and elevated transaminases during lipid-lowering therapies. METHODS This prospective, cohort study enrolled consecutive MAFLD patients with hyperlipidemia and elevated transaminases. Patients were divided into a group receiving lipid-lowering agents and an age-, sex- and baseline lipid level-matched control group without receiving lipid-lowering agents. Clinical visits were performed at the 1st month and then every 3 months for 1 year. RESULTS This study included 541 MAFLD patients (lipid-lowering group: 325 patients; control group: 216 patients). Compared with controls, there was a substantially greater reduction in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) in the lipid-lowering group after 12 months (all P < 0.05). The decrease in ALT was positively correlated with the decrease in TC (r = 0.332), TG (r = 0.180), LDL-c (r = 0.253) and apolipoprotein E (ApoE) (r = 0.119), while the decrease in AST was positively correlated with the decrease in TC (r = 0.228) and LDL-c (r = 0.192) (all P<0.05). The greater range of reduction in blood lipids (TC/TG/LDL-c), the higher the transaminase and GGT normalization rate (all P<0.05). Multivariate analysis confirmed that a TG decrease of over 50% remained an independent predictor of transaminase and GGT normalization (OR 2.07, 95% CI 1.12-3.84, P=0.020). CONCLUSION Lipid-lowering to target levels might be beneficial to liver injury improvements in MAFLD patients with dyslipidemia when receiving lipid-lowering agents.
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Affiliation(s)
- Xianhua Liao
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Qianqian Ma
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Tingfeng Wu
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Congxiang Shao
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yansong Lin
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yanhong Sun
- Department of Laboratory of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Shiting Feng
- Department of Radiology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Wei Wang
- Department of Medical Ultrasonics of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Junzhao Ye
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Bihui Zhong
- Department of Gastroenterology of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
- Correspondence: Bihui Zhong; Junzhao Ye, Department of Gastroenterology of the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan II Road, Yuexiu District, Guangzhou, 510080, People’s Republic of China, Tel +86 135 0307 9262; +86 135 0151 9252, Email ;
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Lee YH, Jang HJ, Kim S, Choi SS, Khim KW, Eom HJ, Hyun J, Shin KJ, Chae YC, Kim H, Park J, Park NH, Woo CY, Hong CH, Koh EH, Nam D, Choi JH. Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA. eLife 2021; 10:70472. [PMID: 34964438 PMCID: PMC8758141 DOI: 10.7554/elife.70472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 12/24/2021] [Indexed: 11/13/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.
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Affiliation(s)
- Yo Han Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hyun-Jun Jang
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Sounkou Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Sun Sil Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Keon Woo Khim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hye-Jin Eom
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jimin Hyun
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Kyeong Jin Shin
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Young Chan Chae
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hongtae Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Chang-Yun Woo
- Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Chung Hwan Hong
- Department of Medical Science, Asan Medical Center, Seoul, Republic of Korea
| | - Eun Hee Koh
- Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Dougu Nam
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jang Hyun Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
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Willis SA, Bawden SJ, Malaikah S, Sargeant JA, Stensel DJ, Aithal GP, King JA. The role of hepatic lipid composition in obesity-related metabolic disease. Liver Int 2021; 41:2819-2835. [PMID: 34547171 DOI: 10.1111/liv.15059] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/15/2021] [Accepted: 09/17/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.
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Affiliation(s)
- Scott A Willis
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Stephen J Bawden
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK
| | - Sundus Malaikah
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jack A Sargeant
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester, UK
| | - David J Stensel
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - James A King
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
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Dixit G, Prabhu A. The pleiotropic peroxisome proliferator activated receptors: Regulation and therapeutics. Exp Mol Pathol 2021; 124:104723. [PMID: 34822814 DOI: 10.1016/j.yexmp.2021.104723] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
The Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolic events in our body. Owing to their implication in maintenance of homeostasis, both PPAR agonists and antagonists assume therapeutic significance. Understanding the molecular mechanisms of each of the PPAR isotypes in the healthy body and during disease is crucial to exploiting their full therapeutic potential. This article is an attempt to present a rational analysis of the multifaceted therapeutic effects and underlying mechanisms of isotype-specific PPAR agonists, dual PPAR agonists, pan PPAR agonists as well as PPAR antagonists. A holistic understanding of the mechanistic dimensions of these key metabolic regulators will guide future efforts to identify novel molecules in the realm of metabolic, inflammatory and immunotherapeutic diseases.
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Affiliation(s)
- Gargi Dixit
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Arati Prabhu
- Department of Pharmaceutical Chemistry & Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
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Albert SG, Wood EM. Meta-analysis of trials in non-alcoholic fatty liver disease with therapeutic interventions for metabolic syndrome. Diabetes Metab Syndr 2021; 15:102232. [PMID: 34352720 DOI: 10.1016/j.dsx.2021.102232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/22/2021] [Accepted: 07/24/2021] [Indexed: 12/27/2022]
Abstract
AIMS Non-alcoholic fatty liver disease [NAFLD] is associated with metabolic syndrome [MS]. Current guidelines restrict therapy for NAFLD, other than weight loss, in early non-fibrotic disease. It was postulated that intervention with therapies for MS may improve liver fat content. METHODS A systematic evaluation of Cochrane and PubMed databases was performed for NAFLD or NASH if they were: 1) interventions for metabolic syndrome or diabetes mellitus 2) randomized controlled trials [RCT], with 3) primary outcomes of liver fat content [LFC] (by magnetic resonance spectroscopy [MRS] or liver biopsy (Nonalcoholic Fatty Liver Disease Activity Score [NAS]). RESULTS There were 30 RCT (in 24 publications) of 2409 subjects. LFC decreased with pioglitazone (MRS, -8.0 ± 1.0 %, p < 0.001), diet and exercise (-7.8 ± 1.7 %, p < 0.001) and omega-3 fatty acids (-6.0 ± 2.5 %, p = 0.02). Decreases in NAS scores were significant for pioglitazone (-1.4 ± 0.4 units, p < 0.001) and D&E (-1.0 ± 0.1 units, p < 0.001). Weight loss correlated with improvement in LFC (p < 0.001) and NAS (p < 0.001). Lowered serum triglycerides correlated with final LFC (p < 0.001) and NAS scores (p < 0.001). CONCLUSIONS Therapies of MS with weight loss, antiglycemic and triglyceride lowering medicines improved LFC and NAS scores. Further studies are necessary to demonstrate if these therapies would pre-emptively limit progression of disease.
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Affiliation(s)
- Stewart G Albert
- Department of Internal Medicine, Division of Endocrinology, Saint Louis University School of Medicine, USA.
| | - Emily M Wood
- Department of Internal Medicine, Division of Endocrinology, Saint Louis University School of Medicine, USA
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Elsayed HRH, El-Nablaway M, Khattab BA, Sherif RN, Elkashef WF, Abdalla AM, El Nashar EM, Abd-Elmonem MM, El-Gamal R. Independent of Calorie Intake, Short-term Alternate-day Fasting Alleviates NASH, With Modulation of Markers of Lipogenesis, Autophagy, Apoptosis, and Inflammation in Rats. J Histochem Cytochem 2021; 69:575-596. [PMID: 34448436 PMCID: PMC8427931 DOI: 10.1369/00221554211041607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a worldwide health problem. Alternate-day fasting (ADF), although thought to be aggressive, has proven safety and efficacy. We aimed to evaluate the effect of short-term ADF against already established high-fat-fructose (HFF)-induced NASH, independent of the amount of calorie intake, and to study the effect of ADF on lipogenesis, apoptosis, and hepatic inflammation. Male Sprague Dawley rats were divided into two groups: (1) negative control and (2) NASH group fed on HFF for 9 weeks, and then randomized into two subgroups of either HFF alone or with ADF protocol for 3 weeks. The ADF could improve HFF-related elevation in serum lactate dehydrogenase and could decrease the mRNA expression of lipogenesis genes; acetyl CoA carboxylase, peroxisome proliferator-activated receptor γ, and peroxisome proliferator-activated receptor α; apoptotic genes caspase-3, p53, and inflammatory cyclo-oxygenase 2; and immunohistochemical staining for their proteins in liver with upregulation of LC3 and downregulation of P62 immunoexpression. Moreover, ADF ameliorated HFF-induced steatosis, inflammation, ballooning, and fibrosis through hematoxylin and eosin, Oil Red O, and Sirius Red staining, confirmed by morphometric analysis, without significant weight loss. Significant correlation of morphometric parameters with levels of gene expression was found. These findings suggest ADF to be a safe effective therapeutic agent in the management of NASH.
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Affiliation(s)
| | | | | | - Rania N. Sherif
- Department of Anatomy and Embryology
- Department of Anatomy, Horus University, New Damietta, Egypt
| | - Wagdi Fawzy Elkashef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Asim Mohammed Abdalla
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Eman Mohammad El Nashar
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Randa El-Gamal
- Department of Medical Biochemistry
- Department of Pathology and Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Smati S, Canivet CM, Boursier J, Cariou B. Anti-diabetic drugs and NASH: from current options to promising perspectives. Expert Opin Investig Drugs 2021; 30:813-825. [PMID: 34214406 DOI: 10.1080/13543784.2021.1951701] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Accumulating evidence supports a bidirectional association between nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). There is a clinical challenge to consider pharmaceutical strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis.Areas covered: By using PubMed, we performed a literature search to review the potential beneficial effect of anti-diabetic and metabolic investigational drugs on NASH.Expert opinion: Since insulin resistance is central in the pathophysiology of both T2D and NASH, there is an urgent need for new insulin sensitizers. Peroxisome proliferator-activated receptor (PPAR) agonists, especially PPARγ and pan-PPARs agonists, have shown some beneficial effects on both NASH and liver fibrosis, but their routine use should be limited by their safety profile. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and the polyagonists (GLP-1, GIP, glucagon) under development are the most promising anti-diabetic drugs for NASH treatment, mainly due to their action on body weight loss. Preliminary, preclinical and early phase studies suggest that SGLT2 inhibitors and fibroblast growth factor (FGF)19 and FGF21-based therapies are promising targets for NASH and T2D treatment. The common weakness for all of these drugs is their limited effect on liver fibrosis, potentially due to short-term trial design.
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Affiliation(s)
- Sarra Smati
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
| | - Clémence M Canivet
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Jérôme Boursier
- Hepato-Gastroenterology department, University Hospital, Angers, France.,HIFIH Laboratory, EA 3859, University of Angers, Angers, France
| | - Bertrand Cariou
- Department of Endocrinology, Université De Nantes, CHU Nantes, CNRS, INSERM, L'institut Du Thorax, Nantes, France
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49
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Orabi D, Berger NA, Brown JM. Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention. Cancers (Basel) 2021; 13:3473. [PMID: 34298687 PMCID: PMC8307710 DOI: 10.3390/cancers13143473] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the rise and becoming a major contributor to the development of hepatocellular carcinoma (HCC). Reasons for this include the rise in obesity and metabolic syndrome in contrast to the marked advances in prevention and treatment strategies of viral HCC. These shifts are expected to rapidly propel this trend even further in the coming decades, with NAFLD on course to become the leading etiology of end-stage liver disease and HCC. No Food and Drug Administration (FDA)-approved medications are currently available for the treatment of NAFLD, and advances are desperately needed. Numerous medications with varying mechanisms of action targeting liver steatosis and fibrosis are being investigated including peroxisome proliferator-activated receptor (PPAR) agonists and farnesoid X receptor (FXR) agonists. Additionally, drugs targeting components of metabolic syndrome, such as antihyperglycemics, have been found to affect NAFLD progression and are now being considered in the treatment of these patients. As NAFLD drug discovery continues, special attention should be given to their relationship to HCC. Several mechanisms in the pathogenesis of NAFLD have been implicated in hepatocarcinogenesis, and therapies aimed at NAFLD may additionally harbor independent antitumorigenic potential. This approach may provide novel prevention and treatment strategies.
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Affiliation(s)
- Danny Orabi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of General Surgery, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Nathan A. Berger
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - J. Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
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Gastaldelli A, Stefan N, Häring HU. Liver-targeting drugs and their effect on blood glucose and hepatic lipids. Diabetologia 2021; 64:1461-1479. [PMID: 33877366 PMCID: PMC8187191 DOI: 10.1007/s00125-021-05442-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/18/2020] [Indexed: 12/16/2022]
Abstract
The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.
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Affiliation(s)
- Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy.
| | - Norbert Stefan
- Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany.
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany.
- German Center for Diabetes Research, Neuherberg, Germany.
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
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