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Amatya R, Joseph A, Roh GS, Moon C, Benmokadem Y, Kim D, Min KA, Shin MC. Combined Esculentin-2CHa Fusion Protein-Coated Au Nanoparticles for Effective Against Non-Alcoholic Fatty Liver Disease in Mice Model. Int J Nanomedicine 2025; 20:3407-3421. [PMID: 40125429 PMCID: PMC11928441 DOI: 10.2147/ijn.s497645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction Extensive research has focused on identifying effective treatments for NAFLD, with numerous bioactive peptide candidates showing significant promise. In this research, a long-acting esculentin-2CHa(1-30)-coated AuNPs (ESC-ABD-AuNPs) was developed and the applicability was evaluated for their use in the treatment of non-alcoholic fatty liver disease (NAFLD). Methods ESC-ABD-AuNPs were synthesized by adopting a 1-step reduction process and the successful preparation of the nanoparticles (NPs) was assessed by various physical characterizations including transmission electron microscopy (TEM), ultraviolet-visible (UV-VIS) absorption spectra, dynamic light scattering (DLS), and Fourier Transform Infrared Spectroscopy (FT-IR). After the ESC-ABD-AuNPs were prepared, cytotoxicity, pharmacokinetics (PK), and biodistribution profiles were identified. Then, with a high-fat diet (HFD)-fed obese mice model, efficacy studies were carried out focused on their effects for anti-hyperglycemia and anti-NAFLD. Furthermore, the feasibility of loading a small molecule onto the NPs was evaluated for potential combination therapy. Results ESC-ABD-AuNPs were synthesized with an average hydrodynamic size of 120 (±10) nm and demonstrated good stability and an extended plasma half-life of 28.3 h. The NPs exhibited high liver accumulation and were well tolerated in cell viability tests. In PK and biodistribution studies, ESC-ABD-AuNPs showed prolonged retention in major organs, such as the pancreas and the liver. Therapeutic efficacy was demonstrated in the HFD-fed obese mice, where the ESC-ABD-AuNPs significantly reduced blood glucose levels, improved glucose tolerance, and mitigated liver fat accumulation. The ESC-ABD-AuNPs platform also showed potential for combination therapies, demonstrated by its ability to load obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, found effective for the treatment of NAFLD in clinical studies. Conclusion Overall, this study has demonstrated the promising potential of ESC-ABD-AuNPs as a novel treatment for NAFLD. This research suggests that ESC-ABD-AuNPs could be a significant advancement in drug delivery and liver disease treatment, particularly for combination therapies.
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Affiliation(s)
- Reeju Amatya
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Amala Joseph
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam, 52727, Republic of Korea
| | - Cheol Moon
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Jeonnam, 57922, Republic of Korea
| | - Yassmine Benmokadem
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Doyeon Kim
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Kyoung Ah Min
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Meong Cheol Shin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
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Tawfeeq HR, Lackey AI, Zhou Y, Diolointzi A, Zacharisen S, Lau YH, Quadro L, Storch J. Tissue-Specific Ablation of Liver Fatty Acid-Binding Protein Induces a Metabolically Healthy Obese Phenotype in Female Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.02.631082. [PMID: 39803463 PMCID: PMC11722216 DOI: 10.1101/2025.01.02.631082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Background/Objectives Obesity is associated with numerous metabolic complications including insulin resistance, dyslipidemia, and a reduced capacity for physical activity. Whole-body ablation of liver fatty acid-binding protein (LFABP) in mice was shown to alleviate several of these metabolic complications; high fat (HF) fed LFABP knockout (LFABP-/-) mice developed higher fat mass than their wild-type (WT) counterparts but displayed a metabolically healthy obese (MHO) phenotype with normoglycemia, normoinsulinemia, and reduced hepatic steatosis compared with WT. LFABP is expressed in both liver and intestine, thus in the present study, LFABP conditional knockout (cKO) mice were generated to determine the contributions of LFABP specifically within the liver or the intestine to the whole body phenotype of the global knockout. Methods Female liver-specific LFABP knockout (LFABPliv-/-), intestine-specific LFABP knockout (LFABPint-/-), and floxed LFABP (LFABPfl/fl) control mice were fed a 45% Kcal fat semipurified HF diet for 12 weeks. Results While not as dramatic as found for whole-body LFABP-/- mice, both LFABPliv-/- and LFABPint-/- mice had significantly higher body weights and fat mass compared with LFABPfl/fl control mice. As with the global LFABP nulls, both LFABPliv-/- and LFABPint-/- mice remained normoglycemic and normoinsulinemic. Despite their greater fat mass, the LFABPliv-/- mice did not develop hepatic steatosis. Additionally, LFABPliv-/- and LFABPint-/- mice had higher endurance exercise capacity when compared with LFABPfl/fl control mice. Conclusions The results suggest, therefore, that either liver-specific or intestine-specific ablation of LFABP in female mice is sufficient to induce, at least in part, the MHO phenotype observed following whole-body ablation of LFABP.
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Affiliation(s)
- Hiba Radhwan Tawfeeq
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Atreju I Lackey
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Yinxiu Zhou
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Anastasia Diolointzi
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
| | - Sophia Zacharisen
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Yin Hei Lau
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
| | - Loredana Quadro
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
- Department of Food Science, Rutgers University, New Brunswick, New Jersey
| | - Judith Storch
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey
- Rutgers Center for Lipid Research, New Brunswick, New Jersey
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Shokri B, Mohebbi H, Mehrabani J. Amelioration of fructose-induced hepatic lipid accumulation by vitamin D 3 supplementation and high-intensity interval training in male Sprague‒Dawley rats. Lipids Health Dis 2024; 23:362. [PMID: 39501326 PMCID: PMC11536532 DOI: 10.1186/s12944-024-02347-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 10/24/2024] [Indexed: 11/09/2024] Open
Abstract
BACKGROUND Intrahepatic lipid accumulation (IHL), a hallmark of metabolic disorders, is closely associated with de novo lipogenesis (DNL). Notably, fructose feeding increased the DNL. Lifestyle modifications resulting from dietary changes and increased physical activity/exercise can decrease the IHL content. We examined the effects of vitamin D3 supplementation (VDS), high-intensity interval training (HIIT), and their combination on the transcription factors and enzymes of the DNL pathway in male Sprague‒Dawley rats fed a high-fructose diet (HFrD). METHODS Forty male rats were assigned to 5 groups (n = 8): CS (the control group had a standard diet); CF (the control group had HFrD (10% (w/v) fructose solution in tap water)); and FT (HFrD + HIIT: 10 bouts of 4 min of high-intensity running, corresponding to 85-90% of the maximal speed with 2 min active rest periods of 50% maximal speed, 5 days per week); FD (HFrD + intervention of intraperitoneal injection of 10000 IU/kg/week VDS); FTD (HFrD + HIIT + VDS) that were maintained for 12 weeks. ELISA, the GOD-POD assay, folch, western blotting, and oil red O staining were used to determine insulin, fasting blood glucose (FBG), hepatic triglyceride (TG) and cholesterol levels; SREBP1c, ChREBP-β, ACC1, FASN, p-ACC1, AMPK, p-AMPK, and PKA protein expression; and IHL content, respectively. RESULTS Both HIIT and VDS led to significant increases in the levels of PKA, AMPK, p-AMPK, and p-ACC1, as well as significant decreases in the levels of SREBP1c, ChREBP-β, ACC1, FASN, insulin, FBG, liver TG, liver cholesterol, and IHL. HIIT exhibited superior efficacy over VDS in reducing ChREBP-β, ACC1, insulin, FBG, liver TG and cholesterol, as well as increasing p-ACC1 and PKA. Notably, the combined intervention of HIIT and VDS yielded the most substantial improvements across all the parameters. CONCLUSIONS HFrD causes IHL accumulation and the onset of diabetes, whereas VDS and HIIT, along with their combined effects, prevent the consequences of HFrD.
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Affiliation(s)
- Behnaz Shokri
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran
| | - Hamid Mohebbi
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran.
| | - Javad Mehrabani
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran
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Xia G, Xu Y, Zhang C, Li M, Li H, Chen C. High levels of serum hypersensitive C-reactive protein are associated with non-alcoholic fatty liver disease in non-obese people: a cross-sectional study. Eur J Med Res 2024; 29:496. [PMID: 39402650 PMCID: PMC11476594 DOI: 10.1186/s40001-024-02065-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 09/13/2024] [Indexed: 10/19/2024] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) and obesity have become one of the most common chronic diseases, and the global prevalence is increasing year by year. Both are accompanied by hypersensitive C-reactive protein (hs-CRP). At present, there are many predictors of NAFLD. Exploring the relationship between hs-CRP and nonalcoholic fatty liver disease in non-obese people will be helpful for risk prediction and clinical screening in high-risk populations. OBJECTIVE To explore the relationship between levels of serum hs-CRP and the presence of NAFLD in non-obese people. METHODS A total of 6558 participants who underwent physical examination from March 2017 to November 2017. Multivariate logistic regression was utilized to analyze the risk factors associated with NAFLD. RESULTS This study including 4240 males and 2318 females ranging from 20 to 94 years. In 1396 patients with NAFLD, the prevalence rate was 21.3%, among which 1056 (24.9%) males and 340 (14.7%) females had NAFLD. The prevalence of NAFLD was much higher in males compared to females (χ2 = 93.748, P < 0.001). In the nonalcoholic fatty liver group, various factors including hs-CRP, age, WC, BMI, systolic blood pressure and blood pressure diastolic blood pressure were significantly higher than those in the control group. Logistic regression analysis confirmed that hs-CRP was an independent risk factor for NAFLD, even after adjusting for relevant variables. CONCLUSIONS The prevalence of NAFLD increases with the level of hs-CRP in both men and women who are non-obese. Hs-CRP levels are an important risk factor for nonalcoholic fatty liver disease in non-obese individuals.
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Affiliation(s)
- Guitao Xia
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China
| | - Yuemei Xu
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China
| | - Cheng Zhang
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China
| | - Mengting Li
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China
| | - Hongliang Li
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China.
| | - Changxi Chen
- Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang Province, China.
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Dayarathne LA, Jasmadi, Ko SC, Yim MJ, Lee JM, Kim JY, Oh GW, Lee DS, Jung WK, Lee SJ, Je JY. Strongylocentrotus intermedius Extract Suppresses Adiposity by Inhibiting Adipogenesis and Promoting Adipocyte Browning via AMPK Activation in 3T3-L1 Cells. J Microbiol Biotechnol 2024; 34:1688-1697. [PMID: 39086228 PMCID: PMC11380521 DOI: 10.4014/jmb.2404.04041] [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: 04/24/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 08/02/2024]
Abstract
The current study aimed to determine whether Strongylocentrotus intermedius (S. intermedius) extract (SIE) exerts anti-obesity potentials employing 3T3-L1 cells as in vitro model. Herein we reported that treatment of SIE for 6 days reduced lipid accretion and triglyceride content whereas it increased the release of free glycerol. The inhibited lipid accumulation and induced lipolysis were evidenced by the downregulation of lipogenesis proteins, such as fatty acid synthase and lipoprotein lipase, and the upregulation of hormone-sensitive lipase expression. Furthermore, the downregulation of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1, highlights that reduced lipid accumulation is supported by lowering adipocyte differentiation. Additionally, treatment activates brown adipocyte phenotype in 3T3-L1 cells by inducing expression of brown adipose tissue-specific proteins, such as uncoupling protein 1 and peroxisome proliferator-activated receptor-γ coactivator 1α. Moreover, SIE induced the phosphorylation of AMP-activated protein kinase (AMPK). The pharmacological approach using AMPK inhibitor revealed that the restraining effect of SIE on adipogenesis and promotion of adipocyte browning were blocked. In GC-MS analysis, SIE was mainly composed of cholest-5-en-3-ol (36.71%) along with saturated and unsaturated fatty acids which have favorable anti-obesity potentials. These results reveal that SIE has the possibility as a lipid-lowering agent for the intervention of obesity.
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Affiliation(s)
- Lakshi A Dayarathne
- Department of Food and Nutrition, Pukyong National University, Busan 48513, Republic of Korea
| | - Jasmadi
- Department of Food and Nutrition, Pukyong National University, Busan 48513, Republic of Korea
- National Research and Innovation Agency, Research Center for Food Technology and Processing, Gunungkidul, 55861, Indonesia
| | - Seok-Chun Ko
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Mi-Jin Yim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Jeong Min Lee
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Ji-Yul Kim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Gun-Woo Oh
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Dae-Sung Lee
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea
| | - Won-Kyo Jung
- Major of Biomedical Engineering, Division of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea
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Hari A, AbdulHameed MDM, Balik-Meisner MR, Mav D, Phadke DP, Scholl EH, Shah RR, Casey W, Auerbach SS, Wallqvist A, Pannala VR. Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis. FRONTIERS IN TOXICOLOGY 2024; 6:1390196. [PMID: 38903859 PMCID: PMC11188372 DOI: 10.3389/ftox.2024.1390196] [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: 02/22/2024] [Accepted: 05/10/2024] [Indexed: 06/22/2024] Open
Abstract
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes (Acadm, Acox1, Cpt2, Cyp4a1-3) and downregulation of lipid transport genes (Apoa1, Apoa5, Pltp). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis (Pck1) and bile acid synthesis (Cyp7a1) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis (Scd) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis.
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Affiliation(s)
- Archana Hari
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Mohamed Diwan M. AbdulHameed
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | | | - Deepak Mav
- Sciome LLC, Research Triangle Park, NC, United States
| | | | | | | | - Warren Casey
- Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Scott S. Auerbach
- Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
| | - Venkat R. Pannala
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
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Khan NN, Zurayyir EJ, Almuslem MY, Alshamrani R, Alamri RA, Sulaimani GHT, Sulimani MHT, Albalawi MSF, Alzehair Alqahani RM, Alanazi EM, Aljawi HH, Alsuliman JA. Anthocyanins as Adjuvant Treatment for Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e63445. [PMID: 39077306 PMCID: PMC11285696 DOI: 10.7759/cureus.63445] [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] [Accepted: 06/28/2024] [Indexed: 07/31/2024] Open
Abstract
Recent studies suggest a role for anthocyanins in the treatment of non-alcoholic fatty liver disease (NAFLD). The purpose of the present review was to assess the effect of anthocyanins as an adjuvant treatment in patients with NAFLD. The literature search was conducted on MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Web of Science, and Scopus without language or time limits up to March 27, 2024. The primary outcomes included the severity of liver fibrosis and the level of liver transaminases. Secondary outcomes included obesity and lipid profile assessments. Standardized mean differences (SMDs) with 95% CIs were calculated for numerical outcomes. Five studies were included. The pooled effect sizes showed lower levels of liver fibrosis and liver transaminases in the anthocyanin group, but the difference was nonsignificant and small in size. The same result was obtained with anthropometric measurements of total cholesterol, low-density lipoprotein, and serum triglycerides, where effect sizes ranged from negligible to medium in magnitude but were all nonsignificant. The anthocyanin group showed a significantly lower body fat percentage (SMD = -0.41 (95%CI: -0.76; -0.06), P = 0.021). Currently, no evidence is available on the efficacy of anthocyanins in improving liver fibrosis or dyslipidemia in patients with NAFLD. There is limited evidence that anthocyanins can lower body fat percentages, but the effect was not reflected in the pooled results of other obesity indices. The few available clinical trials showed several limitations and variations regarding the doses of anthocyanins. Future clinical trials should avoid the limitations of the current studies and provide evidence supporting or refuting the use of anthocyanins in NAFLD patients.
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Affiliation(s)
- Naveed N Khan
- Internal Medicine, King Salman Armed Forces Hospital, Tabuk, SAU
| | | | | | | | | | | | | | | | | | | | - Huda H Aljawi
- Internal Medicine, King Faisal Specialist Hospital & Research Centre, Makkah, SAU
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Sangouni AA, Nadjarzadeh A, Rohani FS, Sharuni F, Zare Z, Rahimpour S, Hojjat H, Hosseinzadeh M. Dietary approaches to stop hypertension (DASH) diet improves hepatic fibrosis, steatosis and liver enzymes in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Eur J Nutr 2024; 63:95-105. [PMID: 37855891 DOI: 10.1007/s00394-023-03221-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/19/2023] [Indexed: 10/20/2023]
Abstract
PURPOSE Recent evidence suggests that adherence to dietary approaches to stop hypertension (DASH) diet can be effective in managing non-alcoholic fatty liver disease (NAFLD). We investigated the effect of DASH diet on hepatic fibrosis, steatosis and liver enzymes in patients with NAFLD. METHODS This 12-week randomized controlled trial was conducted among seventy patients with NAFLD who were randomly assigned into two groups including intervention group (DASH diet containing 50-55% carbohydrate, 15-20% protein, and 30% total fat) and the control group (a healthy diet containing 50-55% carbohydrate, 15-20% protein, and 30% total fat). Both diets were calorie-restricted (500-700 kcal lower than the energy requirement). The primary outcomes included hepatic fibrosis, hepatic steatosis, alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT). RESULTS At the baseline, there was no significant difference between two groups in the level of hepatic fibrosis (P = 0.63), hepatic steatosis (P = 0.53), ALT (P = 0.93), AST (P = 0.18) and GGT (P = 0.76). A significant reduction was found in the intervention group compared to the control group in hepatic fibrosis (23 grades reduction vs. 7 grades reduction; P = 0.008) and hepatic steatosis (31 grades reduction vs. 9 grades reduction; P = 0.03) after intervention. In addition, a significant change was observed in the intervention group compared to control group in ALT ( - 8.50 ± 8.98 vs. - 2.09 ± 7.29; P = 0.002), and AST ( - 5.79 ± 6.83 vs. - 0.51 ± 6.62; P = 0.002). CONCLUSIONS Adherence to DASH diet may be effective in management of NAFLD. TRIAL REGISTRATION The trial was registered on 06 February 2022 at Iranian Registry of Clinical Trials (IRCT20170117032026N3) with URL: https://www.irct.ir/trial/60887 .
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Affiliation(s)
- Abbas Ali Sangouni
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Azadeh Nadjarzadeh
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Sadat Rohani
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Sharuni
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zahra Zare
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Shahab Rahimpour
- Faculty of Medicine, Gastroentrology Department, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hashem Hojjat
- Faculty of Medicine, Department of Radiology, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahdieh Hosseinzadeh
- Research Center for Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Maseko TE, Elkalaf M, Peterová E, Lotková H, Staňková P, Melek J, Dušek J, Žádníková P, Čížková D, Bezrouk A, Pávek P, Červinková Z, Kučera O. Comparison of HepaRG and HepG2 cell lines to model mitochondrial respiratory adaptations in non‑alcoholic fatty liver disease. Int J Mol Med 2024; 53:18. [PMID: 38186319 PMCID: PMC10781417 DOI: 10.3892/ijmm.2023.5342] [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: 06/26/2023] [Accepted: 12/01/2023] [Indexed: 01/09/2024] Open
Abstract
Although some clinical studies have reported increased mitochondrial respiration in patients with fatty liver and early non‑alcoholic steatohepatitis (NASH), there is a lack of in vitro models of non‑alcoholic fatty liver disease (NAFLD) with similar findings. Despite being the most commonly used immortalized cell line for in vitro models of NAFLD, HepG2 cells exposed to free fatty acids (FFAs) exhibit a decreased mitochondrial respiration. On the other hand, the use of HepaRG cells to study mitochondrial respiratory changes following exposure to FFAs has not yet been fully explored. Therefore, the present study aimed to assess cellular energy metabolism, particularly mitochondrial respiration, and lipotoxicity in FFA‑treated HepaRG and HepG2 cells. HepaRG and HepG2 cells were exposed to FFAs, followed by comparative analyses that examained cellular metabolism, mitochondrial respiratory enzyme activities, mitochondrial morphology, lipotoxicity, the mRNA expression of selected genes and triacylglycerol (TAG) accumulation. FFAs stimulated mitochondrial respiration and glycolysis in HepaRG cells, but not in HepG2 cells. Stimulated complex I, II‑driven respiration and β‑oxidation were linked to increased complex I and II activities in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. Exposure to FFAs disrupted mitochondrial morphology in both HepaRG and HepG2 cells. Lipotoxicity was induced to a greater extent in FFA‑treated HepaRG cells than in FFA‑treated HepG2 cells. TAG accumulation was less prominent in HepaRG cells than in HepG2 cells. On the whole, the present study demonstrates that stimulated mitochondrial respiration is associated with lipotoxicity in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. These findings suggest that HepaRG cells are more suitable for assessing mitochondrial respiratory adaptations in the developed in vitro model of early‑stage NASH.
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Affiliation(s)
- Tumisang Edward Maseko
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Moustafa Elkalaf
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Eva Peterová
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Halka Lotková
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Pavla Staňková
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Jan Melek
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Jan Dušek
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, 500 05 Hradec Kralove, Czech Republic
| | - Petra Žádníková
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Dana Čížková
- Department of Histology and Embryology Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Aleš Bezrouk
- Department of Medical Biophysics, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Petr Pávek
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, 500 05 Hradec Kralove, Czech Republic
| | - Zuzana Červinková
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
| | - Otto Kučera
- Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, 500 03 Hradec Kralove, Czech Republic
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10
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Engin A. Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:539-574. [PMID: 39287864 DOI: 10.1007/978-3-031-63657-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic, and it is the most common cause of liver diseases. The patients with severe insulin-resistant diabetes having high body mass index (BMI), high-grade adipose tissue insulin resistance, and high hepatocellular triacylglycerols (triglycerides; TAG) content develop hepatic fibrosis within a 5-year follow-up. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol (DAG), fatty acyl CoA, or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/nonalcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with an increase in saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in the liver tissue of patients with NASH. Hepatocyte lipoapoptosis is a critical feature of NASH. In the "second hit," reduced glutathione levels due to oxidative stress lead to the overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused at least by two ineffectual cyclical pathways. First is the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and the second is the Kelch like-ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. In clinical practice, on ultrasonographic examination, the elevation of transaminases, γ-glutamyltransferase, and the aspartate transaminase to platelet ratio index indicates NAFLD. Fibrosis-4 index, NAFLD fibrosis score, and cytokeratin18 are used for grading steatosis, staging fibrosis, and discriminating the NASH from simple steatosis, respectively. In addition to ultrasonography, "controlled attenuation parameter," "magnetic resonance imaging proton-density fat fraction," "ultrasound-based elastography," "magnetic resonance elastography," "acoustic radiation force impulse elastography imaging," "two-dimensional shear-wave elastography with supersonic imagine," and "vibration-controlled transient elastography" are recommended as combined tests with serum markers in the clinical evaluation of NAFLD. However, to confirm the diagnosis of NAFLD, a liver biopsy is the gold standard. Insulin resistance-associated hyperinsulinemia directly accelerates fibrogenesis during NAFLD development. Although hepatocyte lipoapoptosis is a key driving force of fibrosis progression, hepatic stellate cells and extracellular matrix cells are major fibrogenic effectors. Thereby, these are pharmacological targets of therapies in developing hepatic fibrosis. Nonpharmacological management of NAFLD mainly consists of two alternatives: lifestyle modification and metabolic surgery. Many pharmacological agents that are thought to be effective in the treatment of NAFLD have been tried, but due to lack of ability to attenuate NAFLD, or adverse effects during the phase trials, the vast majority could not be licensed.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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11
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Myint M, Oppedisano F, De Giorgi V, Kim BM, Marincola FM, Alter HJ, Nesci S. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions. J Transl Med 2023; 21:757. [PMID: 37884933 PMCID: PMC10605416 DOI: 10.1186/s12967-023-04627-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 10/14/2023] [Indexed: 10/28/2023] Open
Abstract
Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.
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Affiliation(s)
| | - Francesca Oppedisano
- Department of Health Sciences, Institute of Research for Food Safety and Health, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Valeria De Giorgi
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | | | | | - Harvey J Alter
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | - Salvatore Nesci
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy.
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12
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Wang W, Zhai T, Luo P, Miao X, Wang J, Chen Y. Beneficial effects of silibinin on serum lipids, bile acids, and gut microbiota in methionine-choline-deficient diet-induced mice. Front Nutr 2023; 10:1257158. [PMID: 37867498 PMCID: PMC10587424 DOI: 10.3389/fnut.2023.1257158] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/11/2023] [Indexed: 10/24/2023] Open
Abstract
Background and purpose Silibinin (SIL) is a flavonoid lignin isolated from the fruit and seeds of silybum marianum that exhibits good therapeutic potential for NASH. However, the effects of SIL on serum lipids, bile acids (BAs), and gut microbiota (GM) in NASH mice remain unknown. The present work aimed to explore the beneficial effects of SIL supplementation on serum lipids, bile acids, and gut microbiota in MCD mice. Experimental approach After male C57BL/6 mice were fed with a methionine-choline deficient (MCD) diet and simultaneously gavaged with SIL (20 mg/kg. d) for 8 weeks, the pathological changes of liver tissue were observed by oil red O, haematoxylin-eosin, and Masson tricolor staining; the levels of serum AST and ALT, and liver TG and MDA were detected by assay kits; metabonomics and 16S rDNA sequencing were used to analyze the composition of serum lipids and BAs and the abundance of GM; and the mRNA expression levels of hepatic genes related to BAs homeostasis were detected by RT-qPCR. Results The results indicated that SIL treatment decreased the levels of 26 lipids (including four arachidonic acids, seven FFAs, 12 acyl carnitines, and three GPs) and two BAs (23-DCA, GLCA), while Dubosiella increased the levels of 10 lipids (including TxB3, PG16:0_18:1, Cer t18:0/24:0 and 7 TGs), five BAs (β-MCA, α-MCA, UDCA, 3-oxo-DCA and HCA), and two GMs (Verrucomicrobiota and Akkermansiaceae) of MCD mice, but had no significant effect on the mRNA expression of CYP7A1, CYP27A1, Bsep, Mrp2, Ntcp, or Oatp1b2. Therefore, influencing GM composition and then regulating the levels of serum lipids and BAs through enterohepatic axis should be an important mechanism of SIL-induced alleviative effect on MCD mice. More importantly, we found that SIL had a good coordination in regulating the abundance of GM and the contents of serum lipids and BAs in MCD mice, that is, when the abundance of probiotics was up-regulated, the content of beneficial unsaturated fatty acids in serum was up-regulated, while the serum levels of harmful lipids and BAs were down-regulated. Conclusion The alleviating effect of SIL on NASH may be closely related to the correction of intestinal bacteria disorder, serum bile acid, and lipid metabolic disturbance in mice.
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Affiliation(s)
- Wei Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, China
| | - Ting Zhai
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, China
| | - Ping Luo
- School of Pharmacy, Hubei University of Science and Technology, Xianning, China
| | - Xiaolei Miao
- School of Pharmacy, Hubei University of Science and Technology, Xianning, China
| | - Junjun Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, China
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, China
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13
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Guo T, Yan W, Cui X, Liu N, Wei X, Sun Y, Fan K, Liu J, Zhu Y, Wang Z, Zhang Y, Chen L. Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis. Mol Med 2023; 29:132. [PMID: 37770820 PMCID: PMC10540362 DOI: 10.1186/s10020-023-00721-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD. METHODS Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture. RESULTS Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo. CONCLUSIONS These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis.
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Affiliation(s)
- Tingli Guo
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Wenhui Yan
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xin Cui
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Na Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xiaotong Wei
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Yuzhuo Sun
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - KeXin Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Jieyun Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Yuanyuan Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Zhuanzhuan Wang
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China
| | - Yilei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China.
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Lina Chen
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
- Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China.
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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14
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Weerawatanakorn M, He S, Chang CH, Koh YC, Yang MJ, Pan MH. High Gamma-Aminobutyric Acid (GABA) Oolong Tea Alleviates High-Fat Diet-Induced Metabolic Disorders in Mice. ACS OMEGA 2023; 8:33997-34007. [PMID: 37744823 PMCID: PMC10515172 DOI: 10.1021/acsomega.3c04874] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/16/2023] [Indexed: 09/26/2023]
Abstract
Obesity and overweight are associated with an increasing risk of developing health conditions and chronic non-communicable diseases, including cardiovascular diseases, cancer, musculoskeletal problems, respiratory problems, and mental health, and its prevalence is rising. Diet is one of three primary lifestyle interventions. Many bioactive components in tea especially oolong tea, including flavonoids, gamma-aminobutyric acid (GABA), and caffeine were reported to show related effects in reducing the risk of obesity. However, the effects of GABA oolong tea extracts (OTEs) on high-fat diet (HFD)-induced obesity are still unclear. Therefore, this study aims to explore whether the intervention of GABA OTEs can prevent HFD-induced obesity and decipher its underlying mechanisms using male C57BL/6 J mice. The result indicated that GABA OTEs reduced leptin expression in epididymal adipose tissue and showed a protective effect on nonalcoholic fatty liver disease. It promoted thermogenesis-related protein of uncoupling protein-1 and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), boosted lipid metabolism, and promoted fatty acid oxidation. It also reduced lipogenesis-related protein levels of sterol regulatory element binding protein, acetyl-CoA carboxylase, and fatty acid synthase and inhibited hepatic triglyceride (TG) levels. These data suggest that regular drinking of GABA oolong tea has the potential to reduce the risk of being overweight, preventing obesity development through thermogenesis, lipogenesis, and lipolysis.
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Affiliation(s)
- Monthana Weerawatanakorn
- Department
of Agro-Industry, Naresuan University, 99 Moo 9, Tha Pho, Mueang, Phitsanulok 65000, Thailand
| | - Sang He
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Chun-Han Chang
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Yen-Chun Koh
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Meei-Ju Yang
- Taiwan
Tea Research and Extension Station, Taoyuan 326011, Taiwan
| | - Min-Hsiung Pan
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
- Department
of Medical Research, China Medical University Hospital, China Medical University, Taichung City 40402, Taiwan
- Department
of Health and Nutrition Biotechnology, Asia
University, Taichung City 41354, Taiwan
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15
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Zhai T, Wang J, Chen Y. Honokiol affects the composition of gut microbiota and the metabolism of lipid and bile acid in methionine-choline deficiency diet-induced NASH mice. Sci Rep 2023; 13:15203. [PMID: 37709801 PMCID: PMC10502053 DOI: 10.1038/s41598-023-42358-w] [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: 04/11/2023] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
Honokiol (HNK), one of the main active components of Magnolia officinalis, has a positive effect on non-alcoholic steatohepatitis (NASH). However, the effects of HNK on the composition of serum lipids and bile acids (BAs) and gut microbiota (GM) of NASH mice are still unknown.C57BL/6 mice were fed with methionine-choline deficiency (MCD) diet and gavaged with HNK (20 mg/kg/d) for 8 weeks, then the serum lipids and BAs were detected by LC-MS, the composition of ileum microflora and the mRNA expression of hepatic BAs homeostasis related genes were analyzed by 16S rDNA sequencing and RT-qPCR, respectively. HNK treatment decreased the degree of hepatic lipid drops, inflammatory cell infiltration and fibrosis. Meantime, the serum levels of 34 lipids and 4 BAs in MCD mice were significantly altered by HNK treatment, as well as the increased abundance of Ruminococcaceae, Caulobacteraceae and Brevundimonas, and the decreased abundance of Firmicutes and Dubosiella. Besides, HNK treatment increased the hepatic mRNA expression of Oatp1b2 in MCD mice. The ameliorating effect of HNK on NASH may be partly related to its correction on the disorders of GM, serum lipids and BAs of MCD mice.
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Affiliation(s)
- Ting Zhai
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Junjun Wang
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei University, Wuhan, 430062, China.
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16
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Zhou E, Ge X, Nakashima H, Li R, van der Zande HJP, Liu C, Li Z, Müller C, Bracher F, Mohammed Y, de Boer JF, Kuipers F, Guigas B, Glass CK, Rensen PCN, Giera M, Wang Y. Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation. EMBO Mol Med 2023; 15:e16845. [PMID: 37357756 PMCID: PMC10405065 DOI: 10.15252/emmm.202216845] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/27/2023] Open
Abstract
Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.
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Affiliation(s)
- Enchen Zhou
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
- Department of Cellular and Molecular Medicine and Department of MedicineUniversity of California San DiegoLa JollaCAUSA
| | - Xiaoke Ge
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Hiroyuki Nakashima
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Rumei Li
- Department of PediatricsUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | | | - Cong Liu
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Zhuang Li
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Christoph Müller
- Department of Pharmacy, Center for Drug ResearchLudwig Maximilians UniversityMunichGermany
| | - Franz Bracher
- Department of Pharmacy, Center for Drug ResearchLudwig Maximilians UniversityMunichGermany
| | - Yassene Mohammed
- The Center for Proteomics and MetabolomicsLeiden University Medical CenterLeidenThe Netherlands
| | - Jan Freark de Boer
- Department of PediatricsUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of Laboratory MedicineUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Folkert Kuipers
- Department of PediatricsUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of Laboratory MedicineUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Bruno Guigas
- Department of ParasitologyLeiden University Medical CenterLeidenThe Netherlands
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine and Department of MedicineUniversity of California San DiegoLa JollaCAUSA
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
- Med‐X Institute, Center for Immunological and Metabolic Diseases, and Department of EndocrinologyFirst Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong UniversityXi'anChina
| | - Martin Giera
- The Center for Proteomics and MetabolomicsLeiden University Medical CenterLeidenThe Netherlands
| | - Yanan Wang
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
- Med‐X Institute, Center for Immunological and Metabolic Diseases, and Department of EndocrinologyFirst Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong UniversityXi'anChina
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Rashad Mostafa N, Ali AA, Alkaphoury MG, Marzo RR. <i>Helicobacter Pylori</i> infection and non-alcoholic fatty liver disease. Is there a relationship? HEALTHCARE IN LOW-RESOURCE SETTINGS 2023; 11. [DOI: 10.4081/hls.2023.11379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The most prevalent infection that causes chronic gastritis, gastric ulcers, and gastric cancer is Helicobacter pylori infection. Recent research has implicated H. pylori in the pathogenesis of non-gastrointestinal diseases such as cardiovascular, autoimmune, and metabolic disorders. In addition, since H. pylori is believed to be implicated in insulin resistance, numerous studies have been conducted to determine the relationship between H. pylori infection and nonalcoholic fatty liver diseases (NAFLD), but the results have been contested. The purpose of this study is to determine the relationship between H. Pylori infection and nonalcoholic fatty liver diseases. One hundred patients were examined via urea breath test for the presence of H. pylori infection and vibration-controlled transient elastography for the diagnosis of non-alcoholic fatty liver disease. After adjusting for other variables, age, body mass index (BMI), and H. pylori infection were associated with elastography 248dB/m. Infection with H. pylori contributes to the development of NAFLD, and its eradication may influence prognosis.
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18
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Mukherjee AG, Wanjari UR, Gopalakrishnan AV, Katturajan R, Kannampuzha S, Murali R, Namachivayam A, Ganesan R, Renu K, Dey A, Vellingiri B, Prince SE. Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs. Cells 2022; 11:3959. [PMID: 36552725 PMCID: PMC9777112 DOI: 10.3390/cells11243959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Ramkumar Katturajan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Republic of Korea
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, West Bengal, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda 151401, Punjab, India
| | - Sabina Evan Prince
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
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19
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Duan Y, Luo J, Pan X, Wei J, Xiao X, Li J, Luo M. Association between inflammatory markers and non-alcoholic fatty liver disease in obese children. Front Public Health 2022; 10:991393. [PMID: 36530698 PMCID: PMC9751435 DOI: 10.3389/fpubh.2022.991393] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
Background Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children, non-invasive markers of disease to date are still limited and worth exploring. Objective This study aimed to evaluate the association between inflammatory markers and NAFLD in obese children. Methods We performed a case-control study in Hunan Children's Hospital from September 2020 to September 2021. Study participants were children with obesity diagnosed with NAFLD by abdominal ultrasound examination. Mean platelet volume (MPV), platelet distribution width (PDW), neutrophil, lymphocyte, monocyte, and platelet counts were extracted from medical records and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was performed to evaluate the association between inflammatory markers and NAFLD. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory cytokines for NAFLD. Results Two hundred and sixty-seven obese children were enrolled, including 176 NAFLD patients and 91 simple obesity controls. Multivariable logistic model indicated that increased interleukin (IL)-1β [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.04-1.27], IL-6 (OR = 1.28, 95% CI: 1.07-1.53), and IL-17 (OR = 1.04, 95% CI: 1.02-1.07) levels were significantly associated with NAFLD. In contrast, we observed non-significant associations for IL-8, IL-12, IL-21, IL-32, tumor necrosis factor-α (TNF-α), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), mean platelet volume (MPV), and platelet distribution width (PDW) with NAFLD. The area under the curves (AUCs) of IL-1β, IL-6, and IL-17 to discriminate obese children with or without NAFLD were 0.94, 0.94, and 0.97, respectively. Conclusions Our results indicated that IL-1β, IL-6, and IL-17 levels were significantly associated with NAFLD. These inflammatory cytokines may serve as non-invasive markers to determine the development of NAFLD and potentially identify additional avenues for therapeutic intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jia Wei
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China,*Correspondence: Miyang Luo
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20
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Wei W, Liu L, Liu X, Tao Y, Gong J, Wang Y, Liu S. Black ginseng protects against Western diet-induced nonalcoholic steatohepatitis by modulating the TLR4/NF-κB signaling pathway in mice. J Food Biochem 2022; 46:e14432. [PMID: 36183169 DOI: 10.1111/jfbc.14432] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/18/2022] [Accepted: 09/15/2022] [Indexed: 01/13/2023]
Abstract
Black ginseng (BG) shows beneficial effects on liver injury, but the related mechanism has not been fully revealed. This study attempted to investigate the protective effects and associated mechanisms of BG against nonalcoholic steatohepatitis (NASH). Twelve ginsenosides in BG were annotated by ultrahigh performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The Western diet (WD) together with the low-dose CCl4 was given to mice to create the NASH model. Histopathological examination and liver/serum biochemical analysis revealed that the NASH mice displayed severe steatosis and liver damage compared with control mice. After BG administration, the serum and liver triglycerides (TG) concentrations and the serum level of low-density lipoprotein (LDL) were dramatically reduced. Besides, the BG treatment greatly decreased the serum values of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), and the hepatic expression of fibrotic-related genes, such as alpha-smooth muscle actin (α-SMA) and collagen type I alpha 1 (Col1α1). We further discovered that BG administration could block the protein expression of toll-like receptor 4 (TLR4) and the phosphorylation of nuclear factor-kappa B p65 (NF-κB p65), indicating that BG exerted a liver protective effect via regulating the TLR4/NF-κB pathway. This study demonstrated the therapeutic efficacy and the associated mechanism of BG in the treatment of NASH, giving evidence for BG as a potential functional food to prevent NASH. PRACTICAL APPLICATIONS: BG is a type of processed ginseng product that has been used as diet supplementation and has shown favorable effects on liver injury. However, the pharmacological impact of BG on NASH has not been studied in depth. The present study showed that BG could effectively reduce WD-induced liver fibrosis and inflammation through the TLR4/NF-κB axis, which indicated that BG has the potential to be utilized as a functional herb to attenuate liver injury.
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Affiliation(s)
- Wei Wei
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Liming Liu
- College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin, China
| | - Xiaokang Liu
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Ye Tao
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Jiyu Gong
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, China
| | - Yang Wang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Shuying Liu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
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21
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Latif MU, Schmidt GE, Mercan S, Rahman R, Gibhardt CS, Stejerean-Todoran I, Reutlinger K, Hessmann E, Singh SK, Moeed A, Rehman A, Butt UJ, Bohnenberger H, Stroebel P, Bremer SC, Neesse A, Bogeski I, Ellenrieder V. NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression. Gut 2022; 71:2561-2573. [PMID: 35365570 PMCID: PMC9664107 DOI: 10.1136/gutjnl-2021-325013] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 02/06/2022] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease. DESIGN NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo. RESULTS NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration. CONCLUSION NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.
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Affiliation(s)
- Muhammad Umair Latif
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Geske Elisabeth Schmidt
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Sercan Mercan
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Raza Rahman
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christine Silvia Gibhardt
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Ioana Stejerean-Todoran
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Kristina Reutlinger
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Shiv K Singh
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Abdul Moeed
- Institute for Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Baden-Württemberg, Germany
| | - Abdul Rehman
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Umer Javed Butt
- Clinical Neuroscience, Max-Planck-Institute for Experimental Medicine, Goettingen, Niedersachsen, Germany
| | | | - Philipp Stroebel
- Institute of Pathology, University Medical Center Göttingen, Gottingen, Germany
| | - Sebastian Christopher Bremer
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Ivan Bogeski
- Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany
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22
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Ruan L, Wang G, Qing Lv Z, Li S, Liu Q, Ren Y, Zhang Q, Lv X, Wu R, Ji Z. The effect of varied exercise intensity on antioxidant function, aortic endothelial function, and serum lipids in rats with non-alcoholic fatty liver disease. INVESTIGACIÓN CLÍNICA 2022. [DOI: 10.54817/ic.v63n4a01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
This study aimed to compare the effects of diet and exercise of different intensities on antioxidant function, aortic endothelial cell function and serum lipids in NAFLD (nonalcoholic fatty liver disease) rats. Fifty Sprague-Dawley (SD) rats (180-220g) were randomly divided into two experimental groups and fed either a standard rodent chow diet (CON; n=10) or a high-fat diet (HFD; n=40). After 16 weeks, the animals that received the HFD were randomly separated into a high-fat control group (HFC; n=10) or three ex-ercise training groups: HFD and low-intensity exercise (LE; n=10), HFD and moderate-intensity exercise (ME; n=10), and HFD and incremental intensity exercise (IE; n=10). These experimental rats keep sedentary or trained for the next six weeks. A detection kit was used to detect nitric oxide synthase (NOs), nitric oxide (NO), malondialdehyde (MDA) and other markers of aor-tic oxidative stress. The expression levels of endothelial nitric oxide synthase (e-NOS) and endothelin-1 (ET-1) were detected by immunohistochemistry. TC, TG, and other lipid metabolism parameters were detected by an auto-matic analyzer. Exercise with different intensities could improve lipid me-tabolism, enhance antioxidant function, reduce MDA (P<0.01), increase NO (P<0.01), and improve the expression of e-NOS and ET-1 (P<0.01) protein levels in NAFLD rats. Decreased blood lipids were exhibited in all exercise groups. Notably, the moderate-intensity exercise demonstrated more effecton increasing glutathione (GSH) contents (P<0.01) and decreased the ex-pression of ET-1protein levels (P<0.01). The results showed that exercise at different intensities improved lipid metabolism and enhanced anti-oxidation function. Moderate exercise could improve the function of aortic endothelial cells.
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Affiliation(s)
- Ling Ruan
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Guanghua Wang
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Zhen Qing Lv
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Shoubang Li
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Qin Liu
- College of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Yiling Ren
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Quancheng Zhang
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Xianli Lv
- College of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Rongping Wu
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Zhan Ji
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
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23
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Bassal T, Basheer M, Boulos M, Assy N. Nonalcoholic Fatty Liver Disease-A Concise Review of Noninvasive Tests and Biomarkers. Metabolites 2022; 12:1073. [PMID: 36355154 PMCID: PMC9692389 DOI: 10.3390/metabo12111073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with a continuously growing prevalence. The pathophysiology of the disease is complex and includes several mechanisms, with metabolic syndrome and insulin resistance playing a major role. It is crucial to diagnose NAFLD before it advances to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, presented by its complications which include ascites, portal hypertension, bleeding varices and encephalopathy. Another important complication of NAFLD and cirrhosis is hepatocellular carcinoma (HCC), a cancer with increasing incidence and poor prognosis. Even with the growing prevalence of NAFLD, diagnosis via liver biopsies is unrealistic, considering the costs and complications. Noninvasive tests, including serum biomarkers and elastography, are cost-effective and convenient, thereby replacing liver biopsies in diagnosing and excluding liver fibrosis. However, currently, these noninvasive tests have several limitations, such as variability, inadequate accuracy and risk factors for error. The limitations and variability of these tests comet the investigator to propose combining them in diagnostic algorithms to produce more accurate tools. Identifying patients with significant fibrosis is important for targeted therapies to prevent disease progression. Effective screening using noninvasive tests can be crucial for patient risk stratification and early diagnosis.
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Affiliation(s)
- Tamara Bassal
- Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel
| | - Maamoun Basheer
- Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel
| | - Mariana Boulos
- Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Center, Nahariya 2210001, Israel
- Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 1311502, Israel
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24
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Ahmed ES, Mohamed HE, Farrag MA. Luteolin loaded on zinc oxide nanoparticles ameliorates non-alcoholic fatty liver disease associated with insulin resistance in diabetic rats via regulation of PI3K/AKT/FoxO1 pathway. Int J Immunopathol Pharmacol 2022; 36:3946320221137435. [PMID: 36319192 PMCID: PMC9630902 DOI: 10.1177/03946320221137435] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem with high prevalence and morbidity associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia. Nano-formulation of luteolin with Zn oxide in the form of Lut/ZnO NPs may improve the anti-diabetic property of each alone and ameliorate the insulin resistance thus management of NAFLD. This study aimed to measure the efficiency of Lut/ZnO NPs against insulin resistance coupled with NAFLD and T2DM. METHODS A diabetic rat model with NAFLD was induced by a high-fat diet and streptozotocin (30 mg/kg I.P). Serum diabetogenic markers levels, lipid profile, and activity of liver enzymes were measured beside liver oxidative stress markers. Moreover, the hepatic expressions of PI3K/AKT/FoxO1/SERBP1c as well as heme oxygenase-1 were measured beside the histopathological examination. RESULTS Lut/ZnO NPs treatment effectively reduced hyperglycemia, hyperinsulinemia, and ameliorated insulin resistance. Additionally, Lut/ZnO NPs improved the hepatic functions, the antioxidant system, and reduced the oxidative stress markers. Furthermore, the lipid load in the liver, as well as the circulating TG and TC, was minified via the suppression of lipogenesis and gluconeogenesis. Moreover, Lut/ZnO NPs activated the PI3K/AKT signaling pathway, hence inactivating FoxO1, therefore enhancing the hepatic cells' insulin sensitivity. CONCLUSION Lut/ZnO NPs have a hepatoprotective effect and may relieve the progression of NAFLD by alleviating insulin resistance, ameliorating the antioxidant status, and regulating the insulin signal pathway.
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Affiliation(s)
- Esraa Sa Ahmed
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Hebatallah E Mohamed
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Mostafa A Farrag
- Radiation Biology Research, National Center for Radiation Research and Technology, 68892Egyptian Atomic Energy Authority, Cairo, Egypt
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25
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Yanran W, Jung S, Ko KS. Saturated Fatty Acid-Induced Impairment of Hepatic Lipid Metabolism Is Worsened by Prohibitin 1 Deficiency in Hepatocytes. J Med Food 2022; 25:845-852. [PMID: 35980329 DOI: 10.1089/jmf.2022.k.0028] [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: 11/12/2022] Open
Abstract
Obesity-associated nonalcoholic fatty liver disease (NAFLD) is characterized by excessive intrahepatic lipid accumulation. Despite the increasing prevalence of NAFLD and obesity, the pathogenesis of NAFLD has not yet been clearly elucidated. Prohibitin 1 (PHB1) is mainly expressed in the inner membrane of mitochondria and is known to play an important role in hepatocyte proliferation and lipid metabolism. In this study, we investigated how PHB1 affects lipid metabolism in murine hepatocytes. To reduce the expression of PHB1, Phb1 small interfering RNA was transfected into normal murine hepatocytes (AML12), and the cells were treated with the saturated fatty acid (SFA), palmitic acid (PA), for 24 h. When PHB1 was inhibited, the cell viability decreased by ∼20%, and it was found that it diminished further after PA treatment in both control and peroxisome proliferator-activated receptor gamma (Ppar-γ) knockdown cell groups. Examination of the mRNA expression levels of key enzymes involved in lipid metabolism revealed that PHB1 led to increased stearoyl-coenzyme A desaturase-1 (Scd1) mRNA levels, which leads to an increase in the synthesis of triglycerides (TGs). It also activates the endoplasmic reticulum (ER) stress response through upregulating C/EBP homologous protein (Chop) mRNA levels. PPAR-γ, which has been reported to be upregulated in NAFLD patients, also showed elevated expression. The expression of carnitine palmitoyltransferase 1A, which is involved in the conversion of excess intracellular SFA to fatty acid by catabolism, was downregulated in the PHB1-deficient group. Furthermore, TG synthesis was further promoted by a marked increase in SCD1 mRNA levels, which was further exacerbated by elevated Chop mRNA levels and Ppar-γ disruption. Taken together, PHB1 deficiency led to altered lipid metabolism, resulting in the increased intracellular lipid accumulation and ER stress. These cytotoxic effects were shown to be further exacerbated by excessive PA treatment.
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Affiliation(s)
- Wen Yanran
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
| | - Soohan Jung
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Korea
| | - Kwang Suk Ko
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
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Aljabban J, Rohr M, Syed S, Khorfan K, Borkowski V, Aljabban H, Segal M, Mukhtar M, Mohammed M, Panahiazar M, Hadley D, Spengler R, Spengler E. Transcriptome changes in stages of non-alcoholic fatty liver disease. World J Hepatol 2022; 14:1382-1397. [PMID: 36158924 PMCID: PMC9376779 DOI: 10.4254/wjh.v14.i7.1382] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/29/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.
AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.
METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.
RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset.
CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno , Fresno, CA 93701, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Saint Kitts 1621, Cayon, Saint Kitts and Nevis
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94305, United States
| | - Dexter Hadley
- Department of Artificial Intelligence, Pathology, University of Central Florida College of Medicine , Orlando, FL 32827, United States
| | - Ryan Spengler
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Erin Spengler
- Department of Gastroenterology and Hepatology, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
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Nascè A, Gariani K, Jornayvaz FR, Szanto I. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook. Antioxidants (Basel) 2022; 11:antiox11061131. [PMID: 35740032 PMCID: PMC9219746 DOI: 10.3390/antiox11061131] [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: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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Affiliation(s)
- Alberto Nascè
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
| | - Ildiko Szanto
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
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Velenosi TJ, Ben-Yakov G, Podszun MC, Hercun J, Etzion O, Yang S, Nadal C, Haynes-Williams V, Huang WCA, Gonzalez-Hodar L, Brychta RJ, Takahashi S, Akkaraju V, Krausz KW, Walter M, Cai H, Walter PJ, Muniyappa R, Chen KY, Gonzalez FJ, Rotman Y. Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease. Gastroenterology 2022; 162:1990-2003. [PMID: 35283114 PMCID: PMC9117487 DOI: 10.1053/j.gastro.2022.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD. METHODS In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model. RESULTS There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids. CONCLUSIONS We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.
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Affiliation(s)
- Thomas J. Velenosi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Gil Ben-Yakov
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | - Maren C. Podszun
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | | | | | | | | | | | | | - Lila Gonzalez-Hodar
- Liver & Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH,Liver Diseases Branch, NIDDK, NIH
| | | | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Vikas Akkaraju
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Kristopher W. Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | | | - Hongyi Cai
- Clinical Mass Spectrometry Core, NIDDK, NIH
| | | | | | - Kong Y. Chen
- Diabetes, Endocrinology and Obesity Branch, NIDDK, NIH
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH)
| | - Yaron Rotman
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland; Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland.
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The regulation of HBP1, SIRT1, and SREBP-1c genes and the related microRNAs in non-alcoholic fatty liver rats: The association with the folic acid anti-steatosis. PLoS One 2022; 17:e0265455. [PMID: 35417465 PMCID: PMC9007334 DOI: 10.1371/journal.pone.0265455] [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: 11/18/2021] [Accepted: 03/02/2022] [Indexed: 01/20/2023] Open
Abstract
Folic acid is one of the vital micronutrients that contribute to the genetic stability and other biological activities. In addition, microRNAs regulate gene expression through a multittude of pathways. Our current work aimd to explore the possible ameliorative potency of folic acid and its association with the hepatic miR-21, -34a, and -122 expression as well as their targeted genes, HBP1, SIRT1, and SREBP-1c in rats with non-alcoholic fatty liver disease (NAFL). A total of 50 Wistar rats were randomly divided into two groups, a control group (n = 10) and NAFL group (n = 40). Rats in NAFL group were fed a high-fat diet (HFD) containing 20% fats for 14 weeks. The NAFL group was further subdivided into four groups (n = 10/group), one untreated and three orally folic acid-treated groups (25, 50, and 75 μg/Kg b.wt). NAFL characteristics was evaluated in rats in addition to the miR-21, -34a, and -122 profile as well as the transcriptional levels of HBP1, SIRT1, and SREBP-1c genes. NAFL rats exhibited the classic traits of fatty liver disease profile and dysregulation in the pattern of miR-21, -34a, and -122 expression as well as their targeted genes (HBP1, SIRT1, and SREBP-1c, respectively) in the liver. Additionally, NAFL rats had altered levels of TNF-α and adiponectin. These alterations were significantly ameliorated in a dose-dependent pattern following the folic acid treatments. In conclusions, the anti-steatotic, insulin-sensitizing, glucose-lowering and lipotropic potencies of folic acid in NAFL rats may be linked to the epigenetic modulation of the hepatic microRNAs (miR-21, -34a, and -122) and the expression of their target genes (HBP1, SIRT1, and SREBP-1c).
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Nwakiban Atchan A, Shivashankara ST, Piazza S, Tchamgoue AD, Beretta G, Dell’Agli M, Magni P, Agbor GA, Kuiaté JR, Manjappara UV. Polyphenol-Rich Extracts of Xylopia and Aframomum Species Show Metabolic Benefits by Lowering Hepatic Lipid Accumulation in Diet-Induced Obese Mice. ACS OMEGA 2022; 7:11914-11928. [PMID: 35449947 PMCID: PMC9016817 DOI: 10.1021/acsomega.2c00050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/17/2022] [Indexed: 06/14/2023]
Abstract
Metabolic syndrome is a complex condition associated with a series of pathologies featuring glucose intolerance, diabetes, high blood pressure, dyslipidemia, microalbuminuria, overweight, and obesity. It is also related to nonalcoholic fatty liver disease (NAFLD), recognized as the most familiar cause of chronic liver disease worldwide. The overall prevalence of metabolic syndrome and, consequently, the one of NAFLD is constantly increasing worldwide. The initial management of these diseases involves lifestyle modifications, including changes in diet and physical exercise. In addition to conventional drugs like orlistat, botanicals are traditionally used to counteract these disorders, and some of them are currently under evaluation. The present work evaluated the in vivo beneficial effects of hydroalcoholic extracts of two Cameroonian spices, focusing on obesity-related hepatic lipid injury in high-fat-fed C57BL/6 mice. Hydroethanolic extracts were prepared and characterized by reverse phase-high-performance liquid chromatography (HPLC)-photodiode array detection and ultra performance liquid chromatography-triple time-of-flight electrospray ionization tandem mass spectroscopy (TOF-ESI-MS/MS) analysis. Plant extracts were orally administered for 30 days at different dose levels (100 and 200 mg kg-1 body weight (BW)) to obese C57BL/6 mice. Food intake (FI) and BW were recorded daily. Plasma biochemical parameters and lipid content were estimated at the beginning and at the end of the experiment. Liver tissues were subjected to histological examinations, lipid content, as well as oxidative stress markers, and FAME (fatty acid methyl esters) were estimated. Oral administration of extracts at 200 mg kg-1 BW significantly reduced FI and prevented BW gain. A decrease in the weight of the liver and a decrease in the hepatic and plasma lipid content were observed. Plasma enzyme (serum glutamic-oxaloacetic transaminase, SGOT; serum glutamic pyruvic transaminase, SGPT; alkaline phosphatase, ALP) activities were not indicative of any organ damage. Chemical analysis suggested that phenolic acids (4-caffeoylquinic acid, p-coumaric acid 4-O-glucoside, 5-caffeoylshikimic acid, caffeic acid hexose, and 4-O-methyl gallic acid) and flavonoids (morusin derivatives, naringenin-7-O-glucoside, and homoisoflavanone) identified in the extracts could potentially justify the biological properties observed. The main findings of this study showed that Xylopia parviflora (A. Rich.) Benth and Aframomum citratum (Pereira ex Oliv. et Hanb.) K. Shum decreased hepatic lipid accumulation in high-fat-diet (HFD)-induced obese C57BL/6 mice and confirmed, at least in part, our previous in vitro and ex vivo studies. The molecular mechanisms underlying these effects are still unclear and will be explored in the future.
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Affiliation(s)
| | - Shilpa Talkad Shivashankara
- Department
of Lipid Science, CSIR-Central Food Technological
Research Institute (CFTRI), Mysore 570 020, India
| | - Stefano Piazza
- Department
of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 20133, Italy
| | - Armelle Deutou Tchamgoue
- Centre
for Research on Medicinal Plants and Traditional Medicine, Institute of Medical Research and Medicinal Plants
Studies, P.O. Box 13033, Yaoundé 13033, Cameroon
| | - Giangiacomo Beretta
- Department
of Environmental Science and Policy, Università
degli Studi di Milano, Milan 20133, Italy
| | - Mario Dell’Agli
- Department
of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 20133, Italy
| | - Paolo Magni
- Department
of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 20133, Italy
- IRCCS MultiMedica,
Sesto San Giovanni, Via
Milanese, 300, Sesto San Giovanni, Milan 20099, Italy
| | - Gabriel Agbor Agbor
- Centre
for Research on Medicinal Plants and Traditional Medicine, Institute of Medical Research and Medicinal Plants
Studies, P.O. Box 13033, Yaoundé 13033, Cameroon
| | - Jules-Roger Kuiaté
- Department
of Biochemistry, Faculty of Science, University
of Dschang, P.O. Box 96, Dschang 67, Cameroon
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Sun Z, Tang Z, Yang X, Liu QS, Zhang J, Zhou Q, Jiang G. 3- tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022; 56:3204-3213. [PMID: 35133139 DOI: 10.1021/acs.est.1c07182] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
3-tert-Butyl-4-hydroxyanisole (3-BHA), one of the widely used food antioxidants, has been found to act as a potential obesogen by promoting adipogenesis in vitro and inducing white adipose tissue development in vivo. Whether 3-BHA-induced visceral obesity was accompanied by a disruption of hepatic lipid homeostasis in mammals remained unclear. In this study, we evaluated the effect of 3-BHA on the development of nonalcoholic fatty liver disease (NAFLD) in male C57BL/6J mice. After 18 weeks of oral administration of 10 mg/kg 3-BHA, the mice fed with a high-fat diet (HFD) had higher hepatic triglyceride concentrations (0.32 mg/mg protein) and severer steatosis (1.57 for the NAFLD score) than the control ones. The in vivo hepatic lipid deposition disturbed by 3-BHA was transcriptionally regulated by the genes involved in lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export. The in vitro studies further confirmed that 24 h of exposure to 50 μM 3-BHA could induce intracellular oleic acid (OA) uptake and triglyceride accumulation (1.5-fold of the OA control) in HepG2 cells. Lipidomic analysis indicated the perturbation of 3-BHA in the levels of 30 lipid species related to sphingolipids, glycerophospholipids, and glycerolipids under HFD conditions. The findings herein first revealed the disruption effect of 3-BHA on hepatic lipid homeostasis, thus exacerbating the development of HFD-induced NAFLD.
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Affiliation(s)
- Zhendong Sun
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Zhi Tang
- School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Institute of Environmental Health, Guangdong Medical University, Dongguan, Guangdong 523808, China
| | - Xiaoxi Yang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Qian S Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Jianqing Zhang
- Department of POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Qunfang Zhou
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Guibin Jiang
- School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
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Niu S, Chen S, Chen X, Ren Q, Yue L, Pan X, Zhao H, Li Z, Chen X. Semaglutide ameliorates metabolism and hepatic outcomes in an NAFLD mouse model. Front Endocrinol (Lausanne) 2022; 13:1046130. [PMID: 36568109 PMCID: PMC9780435 DOI: 10.3389/fendo.2022.1046130] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate changes in body weight, liver weight, blood glucose, liver injury markers, pro-inflammatory factors and oxidative stress marker levels in obese mice with HFD induced NAFLD after semaglutide use. PATIENTS AND METHODS The 24 C57BL6J mice were randomly divided into three groups (NCD, HFD and Sema) for the assessment of metabolic status, inflammatory factor and oxidative stress marker levels, liver histopathology in mice. Liver metabolomics was determined by liquid chromatography/mass spectrometry (LC-MS) method. RESULTS The mice body weight, liver weight, blood glucose, TG, TCHO, LDL and pro-inflammatory factors were significantly reduced after semaglutide. Meanwhile, semaglutide increased the SOD level. Semaglutide treatment significantly improved the pathological changes such as hepatocyte steatosis, balloon degeneration and lymphoid foci by HE. It also significantly reduced lipid droplet by Oil Red O. The mitochondria were swollen, the volume increased, the cristae were partially broken and reduced, the intramembrane matrix was partially dissolved, and the mitophagy structure was visible in the visual field. There were 6 metabolites down-regulated and 2 metabolites significantly up-regulated after semaglutide treatment. CONCLUSIONS Semaglutide can reduce blood glucose level and liver fat accumulation and play an anti-inflammatory role in advanced NAFLD that due to the effects of HFD.
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Affiliation(s)
- Shu Niu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xing Chen
- Department of Internal Medical, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Qingjuan Ren
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Lin Yue
- Department of Endocrine, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, China
| | - Xiaoyu Pan
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huiying Zhao
- Department of Endocrine, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China
| | - Zelin Li
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoyi Chen
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
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Therapeutic Effects of Resveratrol on Nonalcoholic Fatty Liver Disease Through Inflammatory, Oxidative Stress, Metabolic, and Epigenetic Modifications. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2021; 2343:19-35. [PMID: 34473313 DOI: 10.1007/978-1-0716-1558-4_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing around the world, in association with the progressive elevation in overweight and obesity. The accumulation of lipids in NAFLD patients contributes to the development of insulin resistance, inflammation and oxidative stress in hepatocytes, and alteration of blood lipids and glycaemia. There are currently no effective pharmacological therapies for NAFLD, although lifestyle and dietary modifications targeting weight reduction are among the prevailing alternative approaches. For this reason, new approaches should be investigated. The natural polyphenol resveratrol represents a potential new treatment for management of NAFLD due to anti-inflammatory and antioxidant properties. Although preclinical trials have demonstrated promising results of resveratrol against NALFD, the lack of conclusive results creates the need for more trials with larger numbers of patients, longer time courses, and standardized protocols.
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34
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Zakaria Z, Othman ZA, Suleiman JB, Che Jalil NA, Ghazali WSW, Nna VU, Mohamed M. Hepatoprotective Effect of Bee Bread in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Rats: Impact on Oxidative Stress and Inflammation. Antioxidants (Basel) 2021; 10:antiox10122031. [PMID: 34943134 PMCID: PMC8698812 DOI: 10.3390/antiox10122031] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/11/2021] [Accepted: 12/15/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a pathological accumulation of hepatic lipid closely linked with many metabolic disorders, oxidative stress and inflammation. We aimed to evaluate the hepatoprotective effect of bee bread on oxidative stress and inflammatory parameters in MAFLD rats. Twenty-eight male Sprague-Dawley rats were assigned into four groups (n = 7/group): normal control (NC), high-fat diet (HFD), bee bread (HFD + Bb, HFD + 0.5 g/kg/day bee bread) and orlistat (HFD + Or, HFD + 10 mg/kg/day orlistat) groups. After 12 weeks, the HFD group demonstrated significantly higher body weight gain, serum levels of lipids (TG, TC, LDL), liver enzymes (AST, ALT, ALP) and adiponectin, liver lipids (TG, TC) and insulin resistance (HOMA-IR). Furthermore, the HFD group showed significantly decreased antioxidant enzyme activities (GPx, GST, GR, SOD, CAT) and GSH level, and increased liver oxidative stress (TBARS, NO), translocation of Nrf2 to the nucleus, Keap1 expression and inflammation (TNF-α, NF-κβ, MCP-1) together with histopathological alterations (steatosis, hepatocyte hypertrophy, inflammatory cell infiltration, collagen deposition), which indicated the presence of non-alcoholic steatohepatitis (NASH) and fibrosis. Bee bread significantly attenuated all these changes exerted by HFD feeding. In conclusion, our results suggest that bee bread might have antioxidant, anti-inflammatory, anti-steatotic and anti-fibrotic effects that are beneficial in protecting liver progression towards NASH and fibrosis.
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Affiliation(s)
- Zaida Zakaria
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (Z.Z.); (Z.A.O.); (W.S.W.G.)
| | - Zaidatul Akmal Othman
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (Z.Z.); (Z.A.O.); (W.S.W.G.)
- Unit of Physiology, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia
| | - Joseph Bagi Suleiman
- Department of Science Laboratory Technology, Akanu Ibiam Federal Polytechnic, Unwana P.M.B. 1007, Ebonyi State, Nigeria;
| | - Nur Asyilla Che Jalil
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Wan Syaheedah Wan Ghazali
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (Z.Z.); (Z.A.O.); (W.S.W.G.)
| | - Victor Udo Nna
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medical Sciences, University of Calabar, Calabar P.M.B. 1115, Nigeria;
| | - Mahaneem Mohamed
- Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia; (Z.Z.); (Z.A.O.); (W.S.W.G.)
- Unit of Integrative Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Correspondence: ; Tel.: +60-97676158
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Bala S, Ganz M, Babuta M, Zhuang Y, Csak T, Calenda CD, Szabo G. Steatosis, inflammasome upregulation, and fibrosis are attenuated in miR-155 deficient mice in a high fat-cholesterol-sugar diet-induced model of NASH. J Transl Med 2021; 101:1540-1549. [PMID: 34453120 PMCID: PMC9272486 DOI: 10.1038/s41374-021-00626-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease globally. miRNAs (miRs) regulate various cellular events that lead to NAFLD. In this study we tested the hypothesis that miR-155 is an important regulator of steatohepatitis and fibrosis pathways. Wild type (WT) or miR-155 deficient (KO) mice received a high fat-high cholesterol-high sugar-diet (HF-HC-HS) for 34 weeks and liver tissues were analyzed. In patients with nonalcoholic steatohepatitis and in the mouse model of HF-HC-HS diet we found increased miR-155 levels in the liver compared to normal livers. Upon HF-HC-HS diet feeding, miR-155 KO mice displayed less liver injury, decreased steatosis, and attenuation in fibrosis compared to WT mice. ALT, triglyceride levels, and genes involved in fatty acid metabolic pathway were increased in WT mice whereas miR-155 KO mice showed attenuation in these parameters. HF-HC-HS diet-induced significant increase in the expression of NLRP3 inflammasome components in the livers of WT mice compared to chow fed diet. Compared to WT mice, miR-155 KO showed attenuated induction in the NLRP3, ASC, and caspase1 inflammasome expression on HF-HC-HS diet. Fibrosis markers such as collagen content and deposition, αSMA, Zeb2, and vimentin were all increased in WT mice and miR-155 KO mice showed attenuated fibrosis marker expression. Overall, our findings highlight a role for miR-155 in HF-HC-HS diet-induced steatosis and liver fibrosis.
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Affiliation(s)
- Shashi Bala
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Michal Ganz
- Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, MA, USA
| | - Mrigya Babuta
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Yuan Zhuang
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Timea Csak
- Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, MA, USA
| | - Charles D Calenda
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA.
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Zhang JW, Pan HT. microRNA profiles of serum exosomes derived from children with nonalcoholic fatty liver. Genes Genomics 2021; 44:879-888. [PMID: 34390467 DOI: 10.1007/s13258-021-01150-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/05/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a chronic disease caused by excessive fat accumulation in the liver in addition to alcohol consumption and other pathological factors. The incidence of NAFLD is rapidly growing, currently affecting 25% of the world population. Exosomes are extracellular vesicles containing a variety of biological molecules, including microRNAs (miRNAs). OBJECTIVE To monitor the expression of exosomal microRNAs in the NAFLD. METHODS In this study, five nonalcoholic fatty liver patients were included in the disease group, and five simple obesity patients were included in the control group. Exosomes from NAFLD patient serum were collected, and exosomal miRNAs were extracted. Exosomes were isolated and then confirmed by electron microscopy, nanoparticle tracking analysis (NTA) and western blotting. High-throughput sequencing methods were used to determine the expression profile of exosome-derived miRNAs. RESULTS The sequencing results revealed that a total of 2588 miRNAs were identified. The expression of 80 miRNAs significantly differed between the NAFLD and control groups, including 30 upregulated and 50 downregulated miRNAs. miR-122-5p, miR-27a, and miR-335-5p may play an important role in NAFLD. Finally, GO and KEGG analyses were applied to explore the function of miRNA targets. CONCLUSIONS Collectively, this study identified some key exosomal miRNAs and pathways in NAFLD that might be used as molecular targets or diagnostic biomarkers for NAFLD.
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Affiliation(s)
- Jian-Wei Zhang
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, 312000, China.,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China
| | - Hai-Tao Pan
- Shaoxing Maternity and Child Health Care Hospital, Shaoxing, 312000, China. .,Obstetrics and Gynecology Hospital of Shaoxing University, Shaoxing, China.
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Rabelo ILA, Arnaud-Sampaio VF, Adinolfi E, Ulrich H, Lameu C. Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor. Cells 2021; 10:1782. [PMID: 34359950 PMCID: PMC8305434 DOI: 10.3390/cells10071782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/17/2022] Open
Abstract
The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients' clinical management's main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.
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Affiliation(s)
- Izadora Lorrany Alves Rabelo
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Vanessa Fernandes Arnaud-Sampaio
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Elena Adinolfi
- Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
| | - Claudiana Lameu
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil; (I.L.A.R.); (V.F.A.-S.); (H.U.)
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38
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Zhang S, Gang X, Yang S, Cui M, Sun L, Li Z, Wang G. The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases. Front Immunol 2021; 12:678355. [PMID: 34322117 PMCID: PMC8311559 DOI: 10.3389/fimmu.2021.678355] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/22/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.
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Affiliation(s)
- Siwen Zhang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Xiaokun Gang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Shuo Yang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Mengzhao Cui
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Lin Sun
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Zhuo Li
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Guixia Wang
- Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China
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Khatiwada S, Lecomte V, Fenech MF, Morris MJ, Maloney CA. Effects of Micronutrient Supplementation on Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced Obesity. Cells 2021; 10:1751. [PMID: 34359921 PMCID: PMC8304500 DOI: 10.3390/cells10071751] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/26/2021] [Accepted: 07/06/2021] [Indexed: 11/17/2022] Open
Abstract
Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.
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Affiliation(s)
- Saroj Khatiwada
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (S.K.); (V.L.); (M.J.M.)
| | - Virginie Lecomte
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (S.K.); (V.L.); (M.J.M.)
| | - Michael F. Fenech
- School of Pharmacy and Medical Sciences, University of South Australia, 108 North Terrace, Adelaide, SA 5001, Australia;
| | - Margaret J. Morris
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (S.K.); (V.L.); (M.J.M.)
| | - Christopher A. Maloney
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (S.K.); (V.L.); (M.J.M.)
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Seidu T, McWhorter P, Myer J, Alamgir R, Eregha N, Bogle D, Lofton T, Ecelbarger C, Andrisse S. DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice. J Endocrinol 2021; 250:49-65. [PMID: 34060475 PMCID: PMC8240729 DOI: 10.1530/joe-21-0040] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
Hyperandrogenemia (HA) is a hallmark of polycystic ovary syndrome (PCOS) and is an integral element of non-alcoholic fatty liver disease (NALFD) in females. Administering low-dose dihydrotestosterone (DHT) induced a normal weight PCOS-like female mouse model displaying NAFLD. The molecular mechanism of HA-induced NAFLD has not been fully determined. We hypothesized that DHT would regulate hepatic lipid metabolism via increased SREBP1 expression leading to NAFLD. We extracted liver from control and low-dose DHT female mice; and performed histological and biochemical lipid profiles, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver compared to controls. However, DHT did not alter the levels of SREBP2 in the liver. DHT mice displayed increased SCAP protein expression and SCAP-SREBP1 binding compared to controls. DHT mice exhibited increased AR binding to intron-8 of SCAP leading to increased SCAP mRNA compared to controls. FAS mRNA and protein expression was increased in the liver of DHT mice compared to controls. p-ACC levels were unaltered in the liver. Other lipid metabolism pathways were examined in the liver, but no changes were observed. Our findings support evidence that DHT increased de novo lipogenic proteins resulting in increased hepatic lipid content via regulation of SREBP1 in the liver. We show that in the presence of DHT, the SCAP-SREBP1 interaction was elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action may be increased AR binding to an ARE in SCAP intron-8.
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Affiliation(s)
- Tina Seidu
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Patrick McWhorter
- Department of Chemistry, Youngstown State University, Youngstown, Ohio, USA
| | - Jessie Myer
- Department of Biology, University of Missouri, Columbia, Missouri, USA
| | - Rabita Alamgir
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Nicole Eregha
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Dilip Bogle
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Taylor Lofton
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Stanley Andrisse
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
- Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Correspondence should be addressed to S Andrisse:
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Xu Z, Lin S, Gong J, Feng P, Cao Y, Li Q, Jiang Y, You Y, Tong Y, Wang P. Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation. Front Med (Lausanne) 2021; 8:681391. [PMID: 34179049 PMCID: PMC8219931 DOI: 10.3389/fmed.2021.681391] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/18/2021] [Indexed: 12/30/2022] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear. Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests. Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD. Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2. Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.
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Affiliation(s)
- Zijin Xu
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Susu Lin
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Junjie Gong
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Peishi Feng
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Yifeng Cao
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Qiaoqiao Li
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Yuli Jiang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Ya You
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Yingpeng Tong
- School of Life Sciences, Taizhou University, Taizhou, China
| | - Ping Wang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
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Hamilton MC, Heintz MM, Pfohl M, Marques E, Ford L, Slitt AL, Baldwin WS. Increased toxicity and retention of perflourooctane sulfonate (PFOS) in humanized CYP2B6-Transgenic mice compared to Cyp2b-null mice is relieved by a high-fat diet (HFD). Food Chem Toxicol 2021; 152:112175. [PMID: 33838175 PMCID: PMC8154739 DOI: 10.1016/j.fct.2021.112175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/24/2021] [Accepted: 03/30/2021] [Indexed: 01/11/2023]
Abstract
PFOS is a persistent, fluorosurfactant used in multiple products. Murine Cyp2b's are induced by PFOS and high-fat diets (HFD) and therefore we hypothesized that human CYP2B6 may alleviate PFOS-induced steatosis. Cyp2b-null and hCYP2B6-Tg mice were treated with 0, 1, or 10 mg/kg/day PFOS by oral gavage for 21-days while provided a chow diet (ND) or HFD. Similar to murine Cyp2b10, CYP2B6 is inducible by PFOS. Furthermore, three ND-fed hCYP2B6-Tg females treated with 10 mg/kg/day PFOS died during the exposure period; neither Cyp2b-null nor HFD-fed mice died. hCYP2B6-Tg mice retained more PFOS in serum and liver than Cyp2b-null mice presumably causing the observed toxicity. In contrast, serum PFOS retention was reduced in the HFD-fed hCYP2B6-Tg mice; the opposite trend observed in HFD-fed Cyp2b-null mice. Hepatotoxicity biomarkers, ALT and ALP, were higher in PFOS-treated mice and repressed by a HFD. However, PFOS combined with a HFD exacerbated steatosis in all mice, especially in the hCYP2B6-Tg mice with significant disruption of key lipid metabolism genes such as Srebp1, Pparg, and Hmgcr. In conclusion, CYP2B6 is induced by PFOS but does not alleviate PFOS toxicity presumably due to increased retention. CYP2B6 protects from PFOS-mediated steatosis in ND-fed mice, but increases steatosis when co-treated with a HFD.
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Affiliation(s)
- Matthew C Hamilton
- Environmental Toxicology Program, Clemson University, Clemson, SC, 29634, USA
| | - Melissa M Heintz
- Environmental Toxicology Program, Clemson University, Clemson, SC, 29634, USA
| | - Marisa Pfohl
- College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA
| | - Emily Marques
- College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA
| | - Lucie Ford
- College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA
| | - Angela L Slitt
- College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA
| | - William S Baldwin
- Environmental Toxicology Program, Clemson University, Clemson, SC, 29634, USA.
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Carreres L, Jílková ZM, Vial G, Marche PN, Decaens T, Lerat H. Modeling Diet-Induced NAFLD and NASH in Rats: A Comprehensive Review. Biomedicines 2021; 9:biomedicines9040378. [PMID: 33918467 PMCID: PMC8067264 DOI: 10.3390/biomedicines9040378] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, characterized by hepatic steatosis without any alcohol abuse. As the prevalence of NAFLD is rapidly increasing worldwide, important research activity is being dedicated to deciphering the underlying molecular mechanisms in order to define new therapeutic targets. To investigate these pathways and validate preclinical study, reliable, simple and reproducible tools are needed. For that purpose, animal models, more precisely, diet-induced NAFLD and nonalcoholic steatohepatitis (NASH) models, were developed to mimic the human disease. In this review, we focus on rat models, especially in the current investigation of the establishment of the dietary model of NAFLD and NASH in this species, compiling the different dietary compositions and their impact on histological outcomes and metabolic injuries, as well as external factors influencing the course of liver pathogenesis.
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Affiliation(s)
- Lydie Carreres
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Zuzana Macek Jílková
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Guillaume Vial
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Inserm U 1300, Hypoxia PathoPhysiology (HP2), 38000 Grenoble, France
| | - Patrice N. Marche
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
| | - Thomas Decaens
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Service D’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Hervé Lerat
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (L.C.); (Z.M.J.); (P.N.M.); (T.D.)
- Université Grenoble-Alpes, 38000 Grenoble, France;
- Unité Mixte de Service UGA hTAG, Inserm US 046, CNRS UAR 2019, 38700 La Tronche, France
- Correspondence:
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Lipid profile disturbances may predispose psoriatic patients to liver dysfunction. Postepy Dermatol Alergol 2021; 38:310-318. [PMID: 34408599 PMCID: PMC8362751 DOI: 10.5114/ada.2021.106209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 11/28/2019] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION Psoriasis is a chronic inflammatory disease associated with metabolic disturbances and liver dysfunction. Both serum fatty acids (FA) and ceramides (Cer) have structural functions but also are signal molecules that could be involved in the pathogenesis of liver dysfunction. AIM To assess the concentration of the circulating FA and Cer in correlation with the alanine aminotransferase (ALT) blood level in psoriatic patients. In addition, we have examined the relationship between ALT concentration and severity of the disease and inflammation markers. MATERIAL AND METHODS Eighty-five patients with psoriasis and 32 healthy controls were enrolled in the study. Patients were divided into 2 groups according to ALT blood levels. Serum concentration of 14 FA and 14 Cer were measured by gas-liquid chromatography. The results were correlated with the Psoriasis Area and Severity Index (PASI), serum lipid profile, and inflammatory markers. RESULTS We observed higher PASI score (p = 0.01) and higher C-reactive protein (p = 0.02) concentration in the group of psoriatic patients with high ALT. Serum ALT positively correlated with saturated fatty acids (SFA) (p = 0.01, r = 0.27) and SFA/unsaturated fatty acids (UFA) ratio (p = 0.01, r = 0.26). ALT negatively correlated with UFA level (p = 0.008, r = -0.28). Lignoceric ceramide positively correlated with ALT level (r = 0.22; p = 0.045) in psoriatic patients. CONCLUSIONS Patients with severe psoriasis are predisposed to the development of liver dysfunction. We have demonstrated disturbances of serum fatty acid and sphingolipid profile in psoriatic patients, which may trigger liver disease.
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Ruan L, Li F, Li S, Zhang M, Wang F, Lv X, Liu Q. Effect of Different Exercise Intensities on Hepatocyte Apoptosis in HFD-Induced NAFLD in Rats: The Possible Role of Endoplasmic Reticulum Stress through the Regulation of the IRE1/JNK and eIF2 α/CHOP Signal Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6378568. [PMID: 33815655 PMCID: PMC7987464 DOI: 10.1155/2021/6378568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To investigate the impact of different-intensity exercise on lipid metabolism, oxidative stress, hepatocyte injury, and apoptosis and the related protein expression of endoplasmic reticulum stress on nonalcoholic fatty liver disease rats. METHOD 50 male Sprague-Dawley rats, 2 months old, were randomly divided into the normal control (CON) group, high-fat diet (HFD) group, low-intensity exercise (LIE) group, moderate-intensity exercise (MIE) group, and incremental-intensity exercise (IIE) group. Blood lipids were tested by the automatic biochemical analyzer. The changes in liver tissues were observed by hematoxylin-eosin staining (HE). The protein expression of Bax and Bcl-2 was detected by the immunohistochemical method. The apoptosis of hepatocytes was detected by the TUNEL method. The protein expression of GRP78, Caspase-3, IRE1, p-IRE1, JNK1, CHOP, PERK, eIF2α, and ATF4 was detected by Western blotting. RESULTS Our study showed that compared with the HFD group, TG, TC, FFA, and LDL-c were reduced in all exercise groups. The different exercise intensities could reduce the protein expression of ATF4, Bax, and hepatocyte apoptosis. Meanwhile, the antioxidant function and Bcl-2 were increased. However, the moderate-intensity exercise demonstrated more effect on improving the antioxidant capacity and inhibiting hepatocyte apoptosis. Compared with the HFD group, Caspase-3 and JNK were significantly decreased in all exercise groups (P < 0.01) and CHOP was decreased in the LIE and MIE groups (P < 0.05). IRE1, eIF2α, the ratio of p-IRE1/IRE1 (P < 0.01), and ATF4 were decreased (P < 0.05) in the MIE group. Compared with the IIE group, p-IRE1 was decreased (P < 0.05) in the MIE group. GRP78 had no significant difference among the exercise groups. CONCLUSION Exercise at different intensities improved blood lipid and hepatic injury in NAFLD rats. However, the body weight of the rats in each exercise group was not significantly different. Moderate-intensity exercise demonstrated more effect on improving the antioxidant ability and inhibiting hepatocyte apoptosis. The possible mechanism depends on the regulation of endoplasmic reticulum stress signaling pathways IRE1/JNK and eIF2α/CHOP.
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Affiliation(s)
- Ling Ruan
- Department of Physical Education, Xi'an Shiyou University, Xi'an, Shaanxi, China
| | - Fanghui Li
- School of Sports Sciences, Nanjing Normal University, Nanjing, Jiangsu, China
| | - Shoubang Li
- Department of Physical Education, Xi'an Shiyou University, Xi'an, Shaanxi, China
| | - Mingjun Zhang
- School of Sports and Health Sciences, Xi'an Physical Education University, Xi'an, Shaanxi, China
| | - Feng Wang
- Ankang Traditional Chinese Medicine, Ankang, Shaanxi, China
| | - Xianli Lv
- School of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Qin Liu
- School of Physical Education, Ankang University, Ankang, Shaanxi, China
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Deguise MO, Pileggi C, De Repentigny Y, Beauvais A, Tierney A, Chehade L, Michaud J, Llavero-Hurtado M, Lamont D, Atrih A, Wishart TM, Gillingwater TH, Schneider BL, Harper ME, Parson SH, Kothary R. SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2021; 12:354-377.e3. [PMID: 33545428 PMCID: PMC8257458 DOI: 10.1016/j.jcmgh.2021.01.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). METHODS Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used. RESULTS The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia. CONCLUSIONS The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.
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Affiliation(s)
- Marc-Olivier Deguise
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada,Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada
| | - Chantal Pileggi
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada
| | - Yves De Repentigny
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Ariane Beauvais
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Alexandra Tierney
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Lucia Chehade
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada,Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada
| | - Jean Michaud
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Maica Llavero-Hurtado
- Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom,The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Douglas Lamont
- FingerPrints Proteomics Facility, University of Dundee, Dundee, United Kingdom
| | - Abdelmadjid Atrih
- FingerPrints Proteomics Facility, University of Dundee, Dundee, United Kingdom
| | - Thomas M. Wishart
- Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom,The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Thomas H. Gillingwater
- Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom,College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Bernard L. Schneider
- Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland,Bertarelli Foundation Gene Therapy Platform, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva, Switzerland
| | - Mary-Ellen Harper
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada
| | - Simon H. Parson
- Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom,Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Rashmi Kothary
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada,Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada,Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada,Correspondence Address correspondence to: Rashmi Kothary, PhD, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. fax: (613) 737-8803.
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Park SR, Cho CS, Xi J, Kang HM, Lee JH. Holistic characterization of single-hepatocyte transcriptome responses to high-fat diet. Am J Physiol Endocrinol Metab 2021; 320:E244-E258. [PMID: 33103450 PMCID: PMC8260362 DOI: 10.1152/ajpendo.00391.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
During nutritional overload and obesity, hepatocyte function is grossly altered, and a subset of hepatocytes begins to accumulate fat droplets, leading to nonalcoholic fatty liver disease (NAFLD). Recent single-cell studies revealed how nonparenchymal cells, such as macrophages, hepatic stellate cells, and endothelial cells, heterogeneously respond to NAFLD. However, it remains to be characterized how hepatocytes, the major constituents of the liver, respond to nutritional overload in NAFLD. Here, using droplet-based, single-cell RNA sequencing (Drop-seq), we characterized how the transcriptomic landscape of individual hepatocytes is altered in response to high-fat diet (HFD) and NAFLD. We showed that the entire hepatocyte population undergoes substantial transcriptome changes upon HFD, although the patterns of alteration were highly heterogeneous, with zonation-dependent and -independent effects. Periportal (zone 1) hepatocytes downregulated many zone 1-specific marker genes, whereas a small number of genes mediating gluconeogenesis were upregulated. Pericentral (zone 3) hepatocytes also downregulated many zone 3-specific genes; however, they upregulated several genes that promote HFD-induced fat droplet formation, consistent with findings that zone 3 hepatocytes accumulate more lipid droplets. Zone 3 hepatocytes also upregulated ketogenic pathways as an adaptive mechanism to HFD. Interestingly, many of the top HFD-induced genes, which encode proteins regulating lipid metabolism, were strongly co-expressed with each other in a subset of hepatocytes, producing a variegated pattern of spatial co-localization that is independent of metabolic zonation. In conclusion, our data set provides a useful resource for understanding hepatocellular alteration during NAFLD at single cell level.
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Affiliation(s)
- Sung Rye Park
- Department of Molecular and Integrative Physiology and Institute for Gerontology, University of Michigan Medical School, Ann Arbor, Michigan
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Chun-Seok Cho
- Department of Molecular and Integrative Physiology and Institute for Gerontology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jingyue Xi
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Hyun Min Kang
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology and Institute for Gerontology, University of Michigan Medical School, Ann Arbor, Michigan
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Du H, Zhao Y, Yin Z, Wang DW, Chen C. The role of miR-320 in glucose and lipid metabolism disorder-associated diseases. Int J Biol Sci 2021; 17:402-416. [PMID: 33613101 PMCID: PMC7893589 DOI: 10.7150/ijbs.53419] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
Glucose and lipids are important nutrients that provide the majority of energy for each organ to maintain homeostasis of the body. With the continuous improvement in living standards, the incidence of metabolic disorder-associated diseases, such as diabetes, hyperlipidemia, and atherosclerosis, is increasing worldwide. Among them, diabetes, which could be induced by both glucose and lipid metabolic disorders, is one of the five diseases with the highest incidence and mortality worldwide. However, the detailed molecular mechanisms underlying glucose and lipid metabolism disorders and target-organ damage are still not fully defined. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs, which usually affect their target mRNAs in the cytoplasm by post-transcriptional regulation. Previously, we have found that miR-320 contributed to glucose and lipid metabolism via different signaling pathways. Most importantly, we identified that nuclear miR-320 mediated diabetes-induced cardiac dysfunction by activating the transcription of fatty acid metabolic genes to cause lipotoxicity in the heart. Here, we reviewed the roles of miR-320 in glucose and lipid metabolism and target-organ damage.
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Affiliation(s)
| | | | | | | | - Chen Chen
- Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Haberl EM, Pohl R, Rein-Fischboeck L, Höring M, Krautbauer S, Liebisch G, Buechler C. Hepatic lipid profile in mice fed a choline-deficient, low-methionine diet resembles human non-alcoholic fatty liver disease. Lipids Health Dis 2020; 19:250. [PMID: 33298075 PMCID: PMC7727224 DOI: 10.1186/s12944-020-01425-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 11/30/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Emerging data support a role for lipids in non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in humans. With experimental models such data can be challenged or validated. Mice fed a low-methionine, choline-deficient (LMCD) diet develop NASH and, when injected with diethylnitrosamine (DEN), HCC. Here, lipidomic analysis was used to elucidate whether the NASH and HCC associated lipid derangements resemble the lipid profile of the human disease. METHODS Lipids were measured in the liver of mice fed a control or a LMCD diet for 16 weeks. DEN was injected at young age to initiate hepatocarcinogenesis. DEN treatment associated changes of the lipid composition and the tumor lipidome were evaluated. RESULTS LMCD diet fed mice accumulated ceramides and triacylglycerols in the liver. Phospholipids enriched with monounsaturated fatty acids were also increased, whereas hepatic cholesterol levels remained unchanged in the LMCD model. Phosphatidylcholine and lysophosphatidylcholine concentrations declined in the liver of LMCD diet fed mice. The changes of most lipids associated with LMCD diet feeding were similar between water and DEN injected mice. Several polyunsaturated (PU) diacylglycerol species were already low in the liver of DEN injected mice fed the control diet. Tumors developed in the liver of LMCD diet fed mice injected with DEN. The tumor specific lipid profile, however, did not resemble the decrease of ceramides and PU phospholipids, which was consistently described in human HCC. Triacylglycerols declined in the cancer tissues, which is in accordance with a low expression of lipogenic enzymes in the tumors. CONCLUSIONS The LMCD model is suitable to study NASH associated lipid reprogramming. Hepatic lipid profile was modestly modified in the DEN injected mice suggesting a function of these derangements in carcinogenesis. Lipid composition of liver tumors did not resemble the human HCC lipidome, and most notably, lipogenesis and triacylglycerol levels were suppressed.
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Affiliation(s)
- Elisabeth M Haberl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Rebekka Pohl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Lisa Rein-Fischboeck
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Marcus Höring
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
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Minamikawa T, Ichimura-Shimizu M, Takanari H, Morimoto Y, Shiomi R, Tanioka H, Hase E, Yasui T, Tsuneyama K. Molecular imaging analysis of microvesicular and macrovesicular lipid droplets in non-alcoholic fatty liver disease by Raman microscopy. Sci Rep 2020; 10:18548. [PMID: 33122711 PMCID: PMC7596489 DOI: 10.1038/s41598-020-75604-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/16/2020] [Indexed: 12/12/2022] Open
Abstract
Predominant evidence of non-alcoholic fatty liver disease (NAFLD) is the accumulation of excess lipids in the liver. A small group with NAFLD may have a more serious condition named non-alcoholic steatohepatitis (NASH). However, there is a lack of investigation of the accumulated lipids with spatial and molecular information. Raman microscopy has the potential to characterise molecular species and structures of lipids based on molecular vibration and can achieve high spatial resolution at the organelle level. In this study, we aim to demonstrate the feasibility of Raman microscopy for the investigation of NAFLD based on the molecular features of accumulated lipids. By applying the Raman microscopy to the liver of the NASH model mice, we succeeded in visualising the distribution of lipid droplets (LDs) in hepatocytes. The detailed analysis of Raman spectra revealed the difference of molecular structural features of the LDs, such as the degree of saturation of lipids in the LDs. We also found that the inhomogeneous distribution of cholesterol in the LDs depending on the histology of lipid accumulation. We visualised and characterised the lipids of NASH model mice by Raman microscopy at organelle level. Our findings demonstrated that the Raman imaging analysis was feasible to characterise the NAFLD in terms of the molecular species and structures of lipids.
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Affiliation(s)
- Takeo Minamikawa
- Department of Post-LED Photonics Research, Institute of Post-LED Photonics, Tokushima University, 2-1 Minami-Josanjima, Tokushima, 770-8506, Japan. .,Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan. .,PRESTO, Japan Science and Technology Agency (JST), 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan. .,Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.
| | - Mayuko Ichimura-Shimizu
- Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.,Department of Pathology and Laboratory Medicine, Graduate School of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima, 770-8503, Japan
| | - Hiroki Takanari
- Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.,Department of Interdisciplinary Researches for Medicine and Photonics, Institute of Post-LED Photonics, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima, 770-8503, Japan
| | - Yuki Morimoto
- Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.,Department of Pathology and Laboratory Medicine, Graduate School of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima, 770-8503, Japan
| | - Ryosuke Shiomi
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan
| | - Hiroki Tanioka
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan
| | - Eiji Hase
- Department of Post-LED Photonics Research, Institute of Post-LED Photonics, Tokushima University, 2-1 Minami-Josanjima, Tokushima, 770-8506, Japan.,Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan
| | - Takeshi Yasui
- Department of Post-LED Photonics Research, Institute of Post-LED Photonics, Tokushima University, 2-1 Minami-Josanjima, Tokushima, 770-8506, Japan.,Graduate School of Technology, Industrial and Social Sciences, Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.,Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan
| | - Koichi Tsuneyama
- Research Cluster On "Multi-Scale Vibrational Microscopy for Comprehensive Diagnosis and Treatment of Cancer", Tokushima University, 2-1 Minami-Josanjima, Tokushima, Tokushima, 770-8506, Japan.,Department of Pathology and Laboratory Medicine, Graduate School of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima, 770-8503, Japan.,Department of Interdisciplinary Researches for Medicine and Photonics, Institute of Post-LED Photonics, Tokushima University, 3-18-15 Kuramoto, Tokushima, Tokushima, 770-8503, Japan
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