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Ling L, Li R, Xu M, Zhou J, Hu M, Zhang X, Zhang XJ. Species differences of fatty liver diseases: comparisons between human and feline. Am J Physiol Endocrinol Metab 2025; 328:E46-E61. [PMID: 39636211 DOI: 10.1152/ajpendo.00014.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most widespread chronic liver disease that poses significant threats to public health due to changes in dietary habits and lifestyle patterns. The transition from simple steatosis to nonalcoholic steatohepatitis (NASH) markedly increases the risk of developing cirrhosis, hepatocellular carcinoma, and liver failure in patients. However, there is only one Food and Drug Administration-approved therapeutic drug in the world, and the clinical demand is huge. There is significant clinical heterogeneity among patients with NAFLD, and it is challenging to fully understand human NAFLD using only a single animal model. Interestingly, felines, like humans, are particularly prone to spontaneous fatty liver disease. This review summarized and compared the etiology, clinical features, pathological characteristics, and molecular pathogenesis between human fatty liver and feline hepatic lipidosis (FHL). We analyzed the key similarities and differences between those two species, aiming to provide theoretical foundations for developing effective strategies for the treatment of NAFLD in clinics.
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Affiliation(s)
- Like Ling
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Ruilin Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Mengqiong Xu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Junjie Zhou
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Manli Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xin Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
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2
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Mao Z, Ma X, Jing Y, Shen M, Ma X, Zhu J, Liu H, Zhang G, Chen F. Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress. Cell Death Dis 2023; 14:584. [PMID: 37660122 PMCID: PMC10475044 DOI: 10.1038/s41419-023-06095-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 08/06/2023] [Accepted: 08/21/2023] [Indexed: 09/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting the specific characteristics of NAFLD are limited. Ufmylation is a newly found post-translational modification process that involves the attachment of the Ubiquitin-fold modifier 1 (UFM1) protein to its substrates via ufmylation modification system. Ufmylation regulates ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in NAFLD pathogenesis. However, the precise role of ufmylation in NAFLD remains unclear. Herein, we aim to elucidate the impact of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms involved. We observed increased expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models. Upregulation of ufmylation on hepatic proteins appeared to be an adaptive response to hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 resulted in increased lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by wild-type UFBP1 (WT UFBP1) but not by a mutant form of UFBP1 lacking the main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in mice with NAFLD induced by a high fat diet (HFD). We also demonstrated that the downregulation of UFBP1 induced ER stress, whereas the reintroduction or overexpression of UFBP1 alleviated ER stress in a manner dependent on ufmylation in NAFLD. This mechanism could be responsible for the amelioration of aberrant hepatic lipogenesis and insulin resistance in NAFLD. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.
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Affiliation(s)
- Ziming Mao
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China
| | - Xiaowen Ma
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China
| | - Yu Jing
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China
| | - Minyan Shen
- School of Graduate, Bengbu Medical College, Bengbu, Anhui, 233030, China
| | - Xirui Ma
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China
| | - Jing Zhu
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China
| | - Huifang Liu
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
| | - Guangya Zhang
- Department of Cardiology, Shanghai Sixth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200233, China.
| | - Fengling Chen
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, China.
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Green CD, Spiegel S. Preclinical models of non-alcoholic steatohepatitis leading to hepatocellular carcinoma. Adv Biol Regul 2023; 87:100925. [PMID: 36706611 DOI: 10.1016/j.jbior.2022.100925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 01/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and its incidence is increasing due to endemic obesity and the growing burden of non-alcoholic steatohepatitis (NASH) associated liver cancer. Although much is known about the clinical and histological pathology of NASH-driven HCC in humans, its etiology remains unclear and there is a lack of reliable biomarkers and limited effective therapies. Progress has been hampered by the scarcity of standardized animal models that recapitulate the gradual progression of NASH towards HCC observed in humans. Here we review existing mouse models and their suitability for studying NASH-driven HCC with special emphasis on a preclinical model that we recently developed that faithfully mimics all the clinical endpoints of progression of the human disease. Moreover, it is highly translatable, allows the use of gene-targeted mice, and is suitable for gaining knowledge of how NASH progresses to HCC and development of new targets for treatment.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Pichon C, Nachit M, Gillard J, Vande Velde G, Lanthier N, Leclercq IA. Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations. Front Nutr 2022; 9:1051157. [PMID: 36466421 PMCID: PMC9709200 DOI: 10.3389/fnut.2022.1051157] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/31/2022] [Indexed: 12/13/2023] Open
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world. Progression toward non-alcoholic steatohepatitis (NASH) is associated with alterations of skeletal muscle. One plausible mechanism for altered muscle compartment in liver disease is changes in ammonia metabolism. In the present study, we explored the hypothesis that NASH-associated hyperammonemia drives muscle changes as well as liver disease progression. MATERIALS AND METHODS In Alms1-mutant mice (foz/foz) fed a 60% fat diet (HFD) for 12 weeks; we investigated hepatic and muscular ammonia detoxification efficiency. We then tested the effect of an 8 week-long supplementation with L-ornithine L-aspartate (LOLA), a known ammonia-lowering treatment, given after either 4 or 12 weeks of HFD for a preventive or a curative intervention, respectively. We monitored body composition, liver and muscle state by micro computed tomography (micro-CT) as well as muscle strength by four-limb grip test. RESULTS According to previous studies, 12 weeks of HFD induced NASH in all foz/foz mice. Increase of hepatic ammonia production and alterations of urea cycle efficiency were observed, leading to hyperammonemia. Concomitantly mice developed marked myosteatosis. First signs of myopenia occurred after 20 weeks of diet. Early LOLA treatment given during NASH development, but not its administration in a curative regimen, efficiently prevented myosteatosis and muscle quality, but barely impacted liver disease or, surprisingly, ammonia detoxification. CONCLUSION Our study confirms the perturbation of hepatic ammonia detoxification pathways in NASH. Results from the interventional experiments suggest a direct beneficial impact of LOLA on skeletal muscle during NASH development, though it does not improve ammonia metabolism or liver disease.
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Affiliation(s)
- Camille Pichon
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Maxime Nachit
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Justine Gillard
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Greetje Vande Velde
- Department of Imaging and Pathology, Molecular Small Animal Imaging Center, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Nicolas Lanthier
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Kumar S, De Leon EM, Granados J, Whitworth DJ, VandeBerg JL. Monodelphis domestica Induced Pluripotent Stem Cells Reveal Metatherian Pluripotency Architecture. Int J Mol Sci 2022; 23:12623. [PMID: 36293487 PMCID: PMC9604385 DOI: 10.3390/ijms232012623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/13/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Marsupials have been a powerful comparative model to understand mammalian biology. However, because of the unique characteristics of their embryology, marsupial pluripotency architecture remains to be fully understood, and nobody has succeeded in developing embryonic stem cells (ESCs) from any marsupial species. We have developed an integration-free iPSC reprogramming method and established validated iPSCs from two inbred strains of a marsupial, Monodelphis domestica. The monoiPSCs showed a significant (6181 DE-genes) and highly uniform (r2 [95% CI] = 0.973 ± 0.007) resetting of the cellular transcriptome and were similar to eutherian ESCs and iPSCs in their overall transcriptomic profiles. However, monoiPSCs showed unique regulatory architecture of the core pluripotency transcription factors and were more like marsupial epiblasts. Our results suggest that POU5F1 and the splice-variant-specific expression of POU5F3 synergistically regulate the opossum pluripotency gene network. It is plausible that POU5F1, POU5F3 splice variant XM_016427856.1, and SOX2 form a self-regulatory network. NANOG expression, however, was specific to monoiPSCs and epiblasts. Furthermore, POU5F1 was highly expressed in trophectoderm cells, whereas all other pluripotency transcription factors were significantly downregulated, suggesting that the regulatory architecture of core pluripotency genes of marsupials may be distinct from that of eutherians.
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Affiliation(s)
- Satish Kumar
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA
| | - Erica M. De Leon
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA
| | - Jose Granados
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA
| | - Deanne J. Whitworth
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD 4072, Australia
- School of Veterinary Science, University of Queensland, Gatton, QLD 4343, Australia
| | - John L. VandeBerg
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA
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Carvalho-Gontijo R, Han C, Zhang L, Zhang V, Hosseini M, Mekeel K, Schnabl B, Loomba R, Karin M, Brenner DA, Kisseleva T. Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD. Semin Liver Dis 2022; 42:233-249. [PMID: 36001995 PMCID: PMC9662188 DOI: 10.1055/s-0042-1755316] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer. Studies in rodent experimental models and primary cell cultures have demonstrated several common cellular and molecular mechanisms in the pathogenesis and regression of liver fibrosis. Chronic injury and death of hepatocytes cause the recruitment of myeloid cells, secretion of inflammatory and fibrogenic cytokines, and activation of myofibroblasts, resulting in liver fibrosis. In this review, we discuss the role of metabolically injured hepatocytes in the pathogenesis of nonalcoholic steatohepatitis and alcohol-associated liver disease. Specifically, the role of chemokine production and de novo lipogenesis in the development of steatotic hepatocytes and the pathways of steatosis regulation are discussed.
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Affiliation(s)
- Raquel Carvalho-Gontijo
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Cuijuan Han
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Lei Zhang
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Vivian Zhang
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Mojgan Hosseini
- Department of Pathology, University of California, San Diego School of Medicine, La Jolla
| | - Kristin Mekeel
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Rohit Loomba
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Michael Karin
- Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla
| | - David A. Brenner
- Department of Medicine, University of California, San Diego School of Medicine, La Jolla
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego School of Medicine, La Jolla
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7
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Green CD, Weigel C, Brown RDR, Bedossa P, Dozmorov M, Sanyal AJ, Spiegel S. A new preclinical model of western diet-induced progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. FASEB J 2022; 36:e22372. [PMID: 35639028 DOI: 10.1096/fj.202200346r] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/29/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well-characterized clinical and histological pathology for NASH-driven HCC in humans, its etiology remains unclear and there is a deficiency in pre-clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high-fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC-related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH-driven HCC that can be utilized for future molecular mechanistic studies of this disease.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Cynthia Weigel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Ryan D R Brown
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Pierre Bedossa
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.,Liverpat, Paris, France
| | - Mikhail Dozmorov
- Departments of Biostatistics and Pathology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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8
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Muriel P, López-Sánchez P, Ramos-Tovar E. Fructose and the Liver. Int J Mol Sci 2021; 22:6969. [PMID: 34203484 PMCID: PMC8267750 DOI: 10.3390/ijms22136969] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic diseases represent a major challenge in world health. Metabolic syndrome is a constellation of disturbances affecting several organs, and it has been proposed to be a liver-centered condition. Fructose overconsumption may result in insulin resistance, oxidative stress, inflammation, elevated uric acid levels, increased blood pressure, and increased triglyceride concentrations in both the blood and liver. Non-alcoholic fatty liver disease (NAFLD) is a term widely used to describe excessive fatty infiltration in the liver in the absence of alcohol, autoimmune disorders, or viral hepatitis; it is attributed to obesity, high sugar and fat consumption, and sedentarism. If untreated, NAFLD can progress to nonalcoholic steatohepatitis (NASH), characterized by inflammation and mild fibrosis in addition to fat infiltration and, eventually, advanced scar tissue deposition, cirrhosis, and finally liver cancer, which constitutes the culmination of the disease. Notably, fructose is recognized as a major mediator of NAFLD, as a significant correlation between fructose intake and the degree of inflammation and fibrosis has been found in preclinical and clinical studies. Moreover, fructose is a risk factor for liver cancer development. Interestingly, fructose induces a number of proinflammatory, fibrogenic, and oncogenic signaling pathways that explain its deleterious effects in the body, especially in the liver.
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Affiliation(s)
- Pablo Muriel
- Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado Postal 14-740, Mexico City 07300, Mexico;
| | - Pedro López-Sánchez
- Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City 11340, Mexico;
| | - Erika Ramos-Tovar
- Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City 11340, Mexico;
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El-Derany MO, AbdelHamid SG. Upregulation of miR-96-5p by bone marrow mesenchymal stem cells and their exosomes alleviate non-alcoholic steatohepatitis: Emphasis on caspase-2 signaling inhibition. Biochem Pharmacol 2021; 190:114624. [PMID: 34052187 DOI: 10.1016/j.bcp.2021.114624] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 11/29/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) has evolved as the most common and devastating chronic liver disease. This study aimed to explore the underlined mechanism for the therapeutic potentials of bone marrow mesenchymal stem cells (BM-MSCs) and their derived exosomes (BM-MSCs-Exo) in an experimental model of high fat diet (HFD) induced NASH. Rats were fed with HFD for 12 weeks. At the seventh week, BM-MSCs were given at a dose of 1x106 cell i.v., per rat. A total of three doses of BM-MSCs were given per each rat in six weeks. BM-MSCs-Exo were given at a dose of 15, 30 and 120 µg/kg i.v., twice per week for six weeks. Perfect homing to the liver was detected. Beneficial effects were reported to BM-MSCs or BM-MSCs-Exo cotreatment; where the highest anti-steatotic effects were attributed to BM-MSCs-Exo (120 µg/kg) showing significant downregulation of fatty acid synthesis (SREB1, 2, ACC), downregulation in lipid uptake (CD36); accompanied by significant upregulation in fatty acid oxidation (PPARα, CPT1). These events were associated with abrogation of hepatic steatosis and ballooning in HFD-induced NASH. BM-MSCs or BM-MSCs-Exo cotreatment exerted significant anti-apoptotic effects mediated by significant decrease in Bax/Bcl2 ratio. Besides, significant increase in mitochondrial mitophagy genes (Parkin, PINK1, ULK1, BNIP3L, ATG5, ATG7, ATG12) were detected in BM-MSCs or BM-MSCs-Exo cotreated groups. These findings are thought to be modulated through upregulation of miRNA-96-5p which leads to downregulation of its downstream target caspase-2. Being a critical player in NASH development, caspase-2 targeting by miRNA-96-5p could be a promising therapeutic modality to treat NASH.
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Affiliation(s)
- Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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10
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Kim H, Lee DS, An TH, Park HJ, Kim WK, Bae KH, Oh KJ. Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC. Int J Mol Sci 2021; 22:ijms22094495. [PMID: 33925827 PMCID: PMC8123490 DOI: 10.3390/ijms22094495] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.
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Affiliation(s)
- Hyunmi Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Da Som Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
| | - Tae Hyeon An
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Hyun-Ju Park
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
- Correspondence: (K.-H.B.); (K.-J.O.); Tel.: +82-42-860-4268 (K.-H.B.); +82-42-879-8265 (K.-J.O.)
| | - Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (H.K.); (D.S.L.); (T.H.A.); (H.-J.P.); (W.K.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34141, Korea
- Correspondence: (K.-H.B.); (K.-J.O.); Tel.: +82-42-860-4268 (K.-H.B.); +82-42-879-8265 (K.-J.O.)
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11
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Fernandes-da-Silva A, Miranda CS, Santana-Oliveira DA, Oliveira-Cordeiro B, Rangel-Azevedo C, Silva-Veiga FM, Martins FF, Souza-Mello V. Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas. Eur J Nutr 2021; 60:2949-2960. [PMID: 33742254 DOI: 10.1007/s00394-021-02542-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
Obesity challenges lipid and carbohydrate metabolism. The resulting glucolipotoxicity causes endoplasmic reticulum (ER) dysfunction, provoking the accumulation of immature proteins, which triggers the unfolded protein reaction (UPR) as an attempt to reestablish ER homeostasis. When the three branches of UPR fail to correct the unfolded/misfolded proteins, ER stress happens. Excessive dietary saturated fatty acids or fructose exhibit the same impact on the ER stress, induced by excessive ectopic fat accumulation or rising blood glucose levels, and meta-inflammation. These metabolic abnormalities can alleviate through dietary interventions. Many pathways are disrupted in adipose tissue, liver, and pancreas during ER stress, compromising browning and thermogenesis, favoring hepatic lipogenesis, and impairing glucose-stimulated insulin secretion within pancreatic beta cells. As a result, ER stress takes part in obesity, hepatic steatosis, and diabetes pathogenesis, arising as a potential target to treat or even prevent metabolic diseases. The scientific community seeks strategies to alleviate ER stress by avoiding inflammation, apoptosis, lipogenesis suppression, and insulin sensitivity augmentation through pharmacological and non-pharmacological interventions. This comprehensive review aimed to describe the contribution of excessive dietary fat or sugar to ER stress and the impact of this adverse cellular environment on adipose tissue, liver, and pancreas function.
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Affiliation(s)
- Aline Fernandes-da-Silva
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Carolline Santos Miranda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Daiana Araujo Santana-Oliveira
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Brenda Oliveira-Cordeiro
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Camilla Rangel-Azevedo
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Flávia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Fabiane Ferreira Martins
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil.
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12
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Ning K, Lu K, Chen Q, Guo Z, Du X, Riaz F, Feng L, Fu Y, Yin C, Zhang F, Wu L, Li D. Epigallocatechin Gallate Protects Mice against Methionine-Choline-Deficient-Diet-Induced Nonalcoholic Steatohepatitis by Improving Gut Microbiota To Attenuate Hepatic Injury and Regulate Metabolism. ACS OMEGA 2020; 5:20800-20809. [PMID: 32875214 PMCID: PMC7450495 DOI: 10.1021/acsomega.0c01689] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/29/2020] [Indexed: 05/10/2023]
Abstract
Epigallocatechin gallate (EGCG) has been regarded as a protective bioactive polyphenol in green tea against nonalcoholic steatohepatitis (NASH), but the mechanism remains poorly deciphered. Herein, we assessed the role and mechanism of EGCG on gut microbiota and the metabolism in NASH development. Forty-eight male C57BL/6J mice were fed with either a methionine-choline-sufficient diet or a methionine-choline-deficient (MCD) diet with or without EGCG administration for 4 weeks. Liver injury, inflammation, lipid accumulation, and iron overload were examined. 16S ribosomal RNA sequencing was used to detect the fecal microbiome. In our research, we observed that EGCG notably improved MCD-diet-derived gut microbiota dysbiosis, as proved by a distinctively clustered separation from that of the MCD group and by the decrease of the Oxalobacter, Oscillibacter, Coprococcus_1, and Desulfovibrio genera and enrichment of norank_f__Bacteroidales_S24_7_group, Alloprevotella, and Bacteroides. Spearman-correlation heatmap analysis indicated that Bacteroides and Alloprevotella induced by EGCG were strongly negatively correlated with lipid accumulation. Functional enzymes of the gut microbiome were predicted by PICRUSt based on the operation classification unit. The results revealed that 1468 enzymes were involved in various metabolic pathways, and 371 enzymes showed distinct changes between untreated and EGCG-treated mice. Long-chain-fatty-acid-CoA ligase ACSBG played a distinct role in fatty acid metabolism and ferroptosis and was significantly negatively correlated with Bacteroides. Altogether, the salutary effect of EGCG on NASH might be via shifting gut flora and certain enzymes from genera. Our study thus takes a step toward NASH prevention and therapy.
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Affiliation(s)
- Kaiting Ning
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Kaikai Lu
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Qian Chen
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Zizhen Guo
- Shanghai
Jiao Tong University School of Medicine, Shanghai 200025, P. R. China
| | - Xiaojuan Du
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Farooq Riaz
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Lina Feng
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Yuping Fu
- Department
of Cardiology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China
| | - Chunyan Yin
- Department
of Pediatric, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China
| | - Fujun Zhang
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Litao Wu
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
| | - Dongmin Li
- Department
of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P. R. China
- Key
Laboratory of Environment and Genes Related to Diseases (Xi’an
Jiaotong University), Ministry of Education
of China, Xi’an, Shaanxi 710061, P.
R. China
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13
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Dai G, Tan Y, Liu J, Yuan B, Song Q, Liu J, He S. The significance of IL-28B and CK-18 M30 levels in the diagnosis of non-alcoholic steatohepatitis in SD rats. Pathol Res Pract 2020; 216:152901. [PMID: 32143904 DOI: 10.1016/j.prp.2020.152901] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 02/01/2020] [Accepted: 02/26/2020] [Indexed: 02/06/2023]
Abstract
AIMS To investigate the role of IL-28B and CK-18 M30 in the diagnosis of non-alcoholic steatohepatitis (NASH) in rats. METHODS The rat NASH model was constructed by high-fat diet feeding and confirmed by liver tissue pathology analysis. The CK-18 M30, IL-28B, liver function and blood lipid were detected. The pathology of liver tissues was observed by H&E staining. The ROC curves of liver pathological scores, IL-28B, and CK-18 M30 were plotted and the sensitivity/specificity of each index was calculated. RESULTS The liver tissue pathology at the end of the 12th week met NASH diagnostic criteria. The liver pathological scores of NASH model were higher than those of the control group (P < 0.05). Compared with the control group, the body weight of rats in the NASH group was lower (P < 0.05) and the liver index was higher (P < 0.05). Moreover, the serum levels of alanine aminotransferase, triglyceride, low-density lipoprotein, total cholesterol and CK-18 M30 in the NASH group were higher (P < 0.05) and positively correlated with liver pathological scores (P < 0.05), but IL-28B in serum and liver tissue was lower (P < 0.05) and negatively correlated with liver pathological scores (P < 0.05). According to the ROC curves, the sensitivity/specificity of each index was shown as following: liver pathological scores (1.000/1.000), IL-28B of liver tissue (1.000/0.857), serum CK-18 M30 plus IL-28B (0.857/1.000), serum IL-28B (0.857/0.857) and serum CK-18 M30 (1.000/0.857). CONCLUSIONS IL-28B level is related to the pathological changes of livers in SD rats during the development of NASH. The combination of serum CK-18 M30 level and serum IL-28B level may be a promising non-invasive detection method for the diagnosis of NASH.
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Affiliation(s)
- Guangrong Dai
- Department of Gastroenterology, Xi'an Jiaotong University First Affiliated Hospital, Xi'an, 710061, PR China; Department of Gastroenterology, Yanan University Affiliated Hospital, Yanan, 716000, PR China
| | - Yue Tan
- Department of Gastroenterology, Yanan University Affiliated Hospital, Yanan, 716000, PR China.
| | - Jingjing Liu
- Department of Gastroenterology, Yanan University Affiliated Hospital, Yanan, 716000, PR China
| | - Beibei Yuan
- Department of Gastroenterology, Yanan University Affiliated Hospital, Yanan, 716000, PR China
| | - Qinglian Song
- Department of Gastroenterology, Yanan University Affiliated Hospital, Yanan, 716000, PR China
| | - Jiaming Liu
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an, 710061, Shaanxi, PR China
| | - Shuixiang He
- Department of Gastroenterology, Xi'an Jiaotong University First Affiliated Hospital, Xi'an, 710061, PR China.
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14
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Ma J, Yin H, Li M, Deng Y, Ahmad O, Qin G, He Q, Li J, Gao K, Zhu J, Wang B, Wu S, Wang T, Shang J. A Comprehensive Study of High Cholesterol Diet-Induced Larval Zebrafish Model: A Short-Time In Vivo Screening Method for Non-Alcoholic Fatty Liver Disease Drugs. Int J Biol Sci 2019; 15:973-983. [PMID: 31182918 PMCID: PMC6535789 DOI: 10.7150/ijbs.30013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 02/20/2019] [Indexed: 12/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease around the world. However, there is still no drug for NAFLD in the market, the study of potential therapeutic drugs on NAFLD is extraordinarily pressing and urgent. The rodent models for NAFLD drugs' study are always with a long time cost. Therefore, we aim to establish a short-time NAFLD drug screening model. A laboratory-made high cholesterol diet was used on larval zebrafish for 3 weeks to establish the NAFLD screen model. Lipid metabolism, oxidant stress, and pathology were studied to comprehensively demonstrate the whole spectrum of NAFLD on this model. Bezafibrate and pioglitazone were used to evaluate the model. Moreover, mechanism research was performed on this model.The NAFLD larval zebrafish model was established with the comprehensive process of NAFLD. Moreover, multiple index on lipid metabolism, oxidant stress, hepatic steatosis, and hepatic inflammation can be easily tested for drug screening. Furthermore, this model can be used to perform the mechanism research by testing mRNA expression. The NAFLD larval zebrafish model is a comprehensive short-time screening method for NAFLD drugs.
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Affiliation(s)
- Ji Ma
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Hongli Yin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Maoru Li
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Yang Deng
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Owais Ahmad
- School of life sciences, China Pharmaceutical University, Nanjing 211198, China
| | - Guohong Qin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Qiangqiang He
- Qinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, Qinghai Province, China
| | - Jiajing Li
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Kai Gao
- Nanjing Ruiying Runze Biopharmaceutical Technology Co., Inc, Nanjing 210000, China
| | - Junyi Zhu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Bing Wang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Susu Wu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
| | - Tao Wang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Jing Shang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China
- Qinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, Qinghai Province, China
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15
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Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, non-alcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibiting robust NASH-to-HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies.
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16
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Colak Y, Coskunpinar EM, Senates E, Oltulu YM, Yaylim I, Gomleksiz OK, Ozan Tiryakioglu N, Hasturk B, Ekmekci CG, Aydogan HY. Assessment of the rs2645424 C/T single nucleotide polymorphisms in the FDFT1 gene, hepatic expression, and serum concentration of the FDFT in patients with nonalcoholic fatty liver disease. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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17
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Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, Kaufman RJ, Saltiel AR, Karin M. ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell 2018; 175:133-145.e15. [PMID: 30220454 DOI: 10.1016/j.cell.2018.08.020] [Citation(s) in RCA: 242] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 05/11/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.
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Affiliation(s)
- Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Ricard Garcia-Carbonell
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Shinichiro Yamachika
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Peng Zhao
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Debanjan Dhar
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Randal J Kaufman
- Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Alan R Saltiel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
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18
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Patankar JV, Wong CK, Morampudi V, Gibson WT, Vallance B, Ioannou GN, Hayden MR. Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition. Am J Physiol Endocrinol Metab 2018; 314:E418-E432. [PMID: 29066462 PMCID: PMC6008057 DOI: 10.1152/ajpendo.00172.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Both type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH) are associated with reduced hepatic mitochondrial respiratory capacity. Cholic acid (CA) is the predominant 12α-hydroxylated bile acid that regulates hepatic lipid metabolism, and its circulating levels are negatively correlated with insulin resistance. Abolishing CA synthesis via the genetic disruption of the enzyme sterol 12α-hydroxylase ( Cyp8b1-/-) leads in resistance to diabetes and hepatic steatosis. Here, we show that long-term stimulation of hepatic lipogenesis leads to a severe impairment in overall metabolic and respiratory function in control mice ( Cyp8b1+/+) but strikingly not in Cyp8b1-/- mice. Cyp8b1-/- mice are protected from such metabolic impairments associated with T2D and NASH by inhibiting hepatic de novo lipogenic gene and protein expression and altering gut microbiota composition. The protective phenotype is compromised when NASH induction is independent of impairment in de novo lipogenesis (DNL). Consequently, Cyp8b1-/- mice also show a reduction in hepatic inflammation and fibrosis along with a shift in antimicrobial dynamics in the small intestine. Our data show that the altered bile acid composition of Cyp8b1-/- mice preserves metabolic and respiratory function by repressing hepatic DNL and driving favorable changes in gut antimicrobial responses.
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Affiliation(s)
- Jay V Patankar
- Centre for Molecular Medicine and Therapeutics, University of British Columbia , Vancouver, British Columbia , Canada
| | - Chi K Wong
- Child and Family Research Institute, Department of Medical Genetics, University of British Columbia , Vancouver, British Columbia , Canada
| | - Vijay Morampudi
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia , Vancouver, British Columbia , Canada
| | - William T Gibson
- Child and Family Research Institute, Department of Medical Genetics, University of British Columbia , Vancouver, British Columbia , Canada
| | - Bruce Vallance
- Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia , Vancouver, British Columbia , Canada
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington , Seattle, Washington
| | - Michael R Hayden
- Centre for Molecular Medicine and Therapeutics, University of British Columbia , Vancouver, British Columbia , Canada
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19
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Rao A, Kosters A, Mells JE, Zhang W, Setchell KDR, Amanso AM, Wynn GM, Xu T, Keller BT, Yin H, Banton S, Jones DP, Wu H, Dawson PA, Karpen SJ. Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 2017; 8:357ra122. [PMID: 27655848 DOI: 10.1126/scitranslmed.aaf4823] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 08/02/2016] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors [including the nuclear receptor for BAs, farnesoid X receptor (FXR)] play integral roles in regulating whole-body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally restricted apical sodium-dependent BA transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high-fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and messenger RNA (mRNA) expression of BA synthesis genes in liver and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, fibroblast growth factor 15. ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs. ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol concentrations, and improved NAFLD activity score in HFD-fed mice. These changes were associated with reduced hepatic expression of lipid synthesis genes (including liver X receptor target genes) and normalized expression of the central lipogenic transcription factor, Srebp1c Accumulation of hepatic lipids and SREBP1 protein were markedly reduced in HFD-fed Asbt(-/-) mice, providing genetic evidence for a protective role mediated by interruption of the enterohepatic BA circulation. Together, these studies suggest that blocking ASBT function with a luminally restricted inhibitor can improve both hepatic and whole body aspects of NAFLD.
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Affiliation(s)
- Anuradha Rao
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA
| | - Astrid Kosters
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA
| | - Jamie E Mells
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA
| | - Wujuan Zhang
- Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Kenneth D R Setchell
- Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Angelica M Amanso
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA
| | - Grace M Wynn
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA
| | - Tianlei Xu
- Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322, USA
| | | | - Hong Yin
- Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA
| | - Sophia Banton
- Department of Biochemistry, Emory University, 1510 Clifton Road Northeast, Atlanta, GA 30322, USA
| | - Dean P Jones
- Department of Biochemistry, Emory University, 1510 Clifton Road Northeast, Atlanta, GA 30322, USA. Department of Medicine, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA
| | - Hao Wu
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
| | - Paul A Dawson
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA. Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA
| | - Saul J Karpen
- Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA. Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA.
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Krishnan A, Abdullah TS, Mounajjed T, Hartono S, McConico A, White T, LeBrasseur N, Lanza I, Nair S, Gores G, Charlton M. A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2017; 312:G666-G680. [PMID: 28232454 PMCID: PMC6146305 DOI: 10.1152/ajpgi.00213.2016] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 02/14/2017] [Accepted: 02/14/2017] [Indexed: 01/31/2023]
Abstract
The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s-1·ml-1 per unit citrate synthase) than SC mice (17-394 pmol·s-1·ml-1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.
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Affiliation(s)
| | - Tasduq Sheikh Abdullah
- 2Indian Institute of Integrative Medicine, Council of Scientific and Industrial Research, Jammu and Kashmir, India;
| | - Taofic Mounajjed
- 3Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota;
| | - Stella Hartono
- 4Division of Immunology, Mayo Clinic, Rochester, Minnesota;
| | - Andrea McConico
- 5Division of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota;
| | - Thomas White
- 6Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota;
| | - Nathan LeBrasseur
- 6Robert and Arlene Kogod Centre for Aging, Mayo Clinic, Rochester, Minnesota;
| | - Ian Lanza
- 7Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and
| | - Sreekumaran Nair
- 7Division of Endocrinology, Mayo Clinic, Rochester, Minnesota; and
| | - Gregory Gores
- 1Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota;
| | - Michael Charlton
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota; .,Division of Hepatology, Intermountain Healthcare, Salt Lake City, Utah
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Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis. Sci Rep 2017; 7:39764. [PMID: 28051126 PMCID: PMC5209674 DOI: 10.1038/srep39764] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 11/28/2016] [Indexed: 02/08/2023] Open
Abstract
Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes non-alcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-α, PPAR-γ, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE.
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Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 2017; 66:180-190. [PMID: 27646933 DOI: 10.1136/gutjnl-2016-312431] [Citation(s) in RCA: 336] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/29/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023]
Abstract
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.
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Affiliation(s)
- Yaron Rotman
- Liver and Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Anavi S, Eisenberg-Bord M, Hahn-Obercyger M, Genin O, Pines M, Tirosh O. The role of iNOS in cholesterol-induced liver fibrosis. J Transl Med 2015; 95:914-24. [PMID: 26097999 DOI: 10.1038/labinvest.2015.67] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 04/07/2015] [Accepted: 04/28/2015] [Indexed: 01/08/2023] Open
Abstract
Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1α stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.
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Affiliation(s)
- Sarit Anavi
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Michal Eisenberg-Bord
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Michal Hahn-Obercyger
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Olga Genin
- Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
| | - Mark Pines
- Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel
| | - Oren Tirosh
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
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Zelber-Sagi S, Salomone F, Yeshua H, Lotan R, Webb M, Halpern Z, Santo E, Oren R, Shibolet O. Non-high-density lipoprotein cholesterol independently predicts new onset of non-alcoholic fatty liver disease. Liver Int 2014; 34:e128-35. [PMID: 24118857 DOI: 10.1111/liv.12318] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Accepted: 09/02/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk. Non-high-density lipoprotein cholesterol (non-HDL-C), i.e. total cholesterol minus HDL, is a well-established risk factor for CVD; however, its association with NAFLD development has not been established. Our aim was to test whether non-HDL-C is an independent predictor of new onset of NAFLD. METHODS A prospective cohort study of 213 subjects from the general population, without liver disease, was studied. Evaluation of medical history, dietary and physical activity habits, fasting blood tests and ultrasonographic evidence of NAFLD was performed at baseline and after a 7-year follow-up by identical protocols. RESULTS From 147 patients that did not have NAFLD at baseline, 28 (19%) developed NAFLD at the 7-year follow-up. The baseline levels of non-HDL-C were higher among subjects who developed NAFLD (179.5 ± 37.1 vs. 157.3 ± 35.1 mg/dl, P = 0.003). Non-HDL-C independently predicted new onset of NAFLD adjusting for age, gender, BMI or waist circumference, lifestyle and serum insulin (OR = 1.02 for every mg/dl increment, 1.01-1.04 95% CI, P = 0.008). Non-HDL-C was a stronger predictor for NAFLD than total cholesterol, low-density lipoprotein cholesterol, triglycerides and HDL. No patients with non-HDL-C < 130 mg/dl developed NAFLD, whereas 20.8% of those with values between 130 to 160 and 24.6% of those with values >160 mg/dl developed NAFLD (P for trend = 0.015). CONCLUSIONS Non-HDL-C is an independent predictor for NAFLD and a stronger predictor than other lipoproteins. This association may stem from the combined hepato-toxic effect of non-HDL-C and may explain the association between NAFLD and CVD.
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Affiliation(s)
- Shira Zelber-Sagi
- Department Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
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Marzuillo P, Miraglia del Giudice E, Santoro N. Pediatric fatty liver disease: role of ethnicity and genetics. World J Gastroenterol 2014; 20:7347-7355. [PMID: 24966605 PMCID: PMC4064080 DOI: 10.3748/wjg.v20.i23.7347] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 01/04/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs' group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.
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Anavi S, Hahn-Obercyger M, Madar Z, Tirosh O. Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling pathway for liver damage. Free Radic Biol Med 2014; 71:61-69. [PMID: 24632196 DOI: 10.1016/j.freeradbiomed.2014.03.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 02/03/2014] [Accepted: 03/04/2014] [Indexed: 12/12/2022]
Abstract
Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6h), but not after 2h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver.
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Affiliation(s)
- Sarit Anavi
- The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
| | - Michal Hahn-Obercyger
- The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
| | - Zecharia Madar
- The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
| | - Oren Tirosh
- The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
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Voloshin I, Hahn-Obercyger M, Anavi S, Tirosh O. L-arginine conjugates of bile acids-a possible treatment for non-alcoholic fatty liver disease. Lipids Health Dis 2014; 13:69. [PMID: 24750587 PMCID: PMC4021351 DOI: 10.1186/1476-511x-13-69] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 04/09/2014] [Indexed: 12/18/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a continuum of diseases that include simple steatosis and non-alcoholic steatohepatitis (NASH) ultimately leading to cirrhosis, hepatocellular carcinoma and end stage liver failure. Currently there is no approved treatment for NASH. It is known that bile acids not only have physiological roles in lipid digestion but also have strong hormonal properties. We have synthesized a novel chenodeoxycholyl-arginine ethyl ester conjugate (CDCArg) for the treatment of NAFLD. Methods Chemical synthesis of CDCArg was performed. Experiments for prevention and treatment of NAFLD were carried out on C57BL/6 J male mice that were treated with high fat diet (HFD, 60% calories from fat). CDCArg or cholic acid bile acids were admixture into the diets. Food consumption, weight gain, liver histology, intraperitoneal glucose tolerance test, biochemical analysis and blood parameters were assessed at the end of the experiment after 5 weeks of diet (prevention study) or after 14 weeks of diet (treatment study). In the treatment study CDCArg was admixture into the diet at weeks 10–14. Results In comparison to HFD treated mice, mice treated with HFD supplemented with CDCArg, showed reduced liver steatosis, reduced body weight and decreased testicular fat and liver tissue mass. Blood glucose, cholesterol, insulin and leptin levels were also lower in this group. No evidence of toxicity of CDCArg was recorded. In fact, liver injury, as evaluated using plasma hepatic enzyme levels, was low in mice treated with HFD and CDCArg when compared to mice treated with HFD and cholic acid. Conclusion CDCArg supplementation protected the liver against HFD-induced NAFLD without any toxic effects. These results indicate that basic amino acids e.g., L-arginine and bile acids conjugates may be a potential therapy for NAFLD.
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Affiliation(s)
| | | | | | - Oren Tirosh
- Institute of Biochemistry, Food Science and Nutrition, The Robert H, Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, PO Box 12, Rehovot 76100, Israel.
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28
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Farrell G. Should we lower lipids in nonalcoholic fatty liver disease? Clin Gastroenterol Hepatol 2014; 12:152-5. [PMID: 23958558 DOI: 10.1016/j.cgh.2013.07.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/18/2013] [Accepted: 07/22/2013] [Indexed: 01/30/2023]
Affiliation(s)
- Geoffrey Farrell
- Department of Hepatic Medicine, Australian National University Medical School, The Canberra Hospital, Woden, ACT, Australia.
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29
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Van Rooyen DM, Gan LT, Yeh MM, Haigh WG, Larter CZ, Ioannou G, Teoh NC, Farrell GC. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J Hepatol 2013; 59:144-52. [PMID: 23500152 DOI: 10.1016/j.jhep.2013.02.024] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 02/10/2013] [Accepted: 02/25/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS We have recently showed that hyperinsulinemia promotes hepatic free cholesterol (FC) accumulation in obese, insulin-resistant Alms1 mutant (foz/foz) mice with NASH. Here we tested whether cholesterol-lowering drugs reduce stress-activated c-Jun N-terminal kinase (JNK) activation, hepatocyte injury/apoptosis, inflammation, and fibrosis in this metabolic syndrome NASH model. METHODS Female foz/foz and WT mice were fed HF (0.2% cholesterol) 16 weeks, before adding ezetimibe (5 mg/kg), atorvastatin (20 mg/kg), or both to diet, another 8 weeks. Hepatic lipidomic analysis, ALT, liver histology, Sirius Red morphometry, hepatic mRNA and protein expression and immunohistochemistry (IHC) for apoptosis (M30), macrophages (F4/80), and polymorphs (myeloperoxidase) were determined. RESULTS In mice with NASH, ezetimibe/atorvastatin combination normalized hepatic FC but did not alter saturated free fatty acids (FFA) and had minimal effects on other lipids; ezetimibe and atorvastatin had similar but less profound effects. Pharmacological lowering of FC abolished JNK activation, improved serum ALT, apoptosis, liver inflammation/NAFLD activity score, designation as "NASH", macrophage chemotactic protein-1 expression, reduced macrophage and polymorph populations, and liver fibrosis. CONCLUSIONS Cholesterol lowering with ezetimibe/atorvastatin combination reverses hepatic FC but not saturated FFA accumulation. This dampens JNK activation, ALT release, hepatocyte apoptosis, and inflammatory recruitment, with reversal of steatohepatitis pathology and liver fibrosis. Ezetimibe/statin combination is a potent, mechanism-based treatment that could reverse NASH and liver fibrosis.
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Affiliation(s)
- Derrick M Van Rooyen
- Liver Research Group, ANU Medical School at The Canberra Hospital, Garran, ACT, Australia
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In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int J Mol Sci 2013; 14:11963-80. [PMID: 23739675 PMCID: PMC3709766 DOI: 10.3390/ijms140611963] [Citation(s) in RCA: 169] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 05/17/2013] [Accepted: 05/22/2013] [Indexed: 12/28/2022] Open
Abstract
By now, non-alcoholic fatty liver disease (NAFLD) is considered to be among the most common liver diseases world-wide. NAFLD encompasses a broad spectrum of pathological conditions ranging from simple steatosis to steatohepatitis, fibrosis and finally even cirrhosis; however, only a minority of patients progress to end-stages of the disease, and the course of the disease progression to the later stages seems to be slow, developing progressively over several years. Key risk factors including overweight, insulin resistance, a sedentary life-style and an altered dietary pattern, as well as genetic factors and disturbances of the intestinal barrier function have been identified in recent years. Despite intense research efforts that lead to the identification of these risk factors, knowledge about disease initiation and molecular mechanisms involved in progression is still limited. This review summarizes diet-induced and genetic animal models, as well as cell culture models commonly used in recent years to add to the understanding of the mechanisms involved in NAFLD, also referring to their advantages and disadvantages.
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Farrell GC, Wong VWS, Chitturi S. NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013; 10:307-18. [PMID: 23458891 DOI: 10.1038/nrgastro.2013.34] [Citation(s) in RCA: 352] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
NAFLD--regarded as a consequence of the modern sedentary, food-abundant lifestyle prevalent in the West--was recorded in Japan nearly 50 years ago and its changing epidemiology during the past three decades is well-documented. NAFLD, and its pathologically more severe form NASH, occur in genetically susceptible people who are over-nourished. Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle. Community prevalence ranges between 20% (China), 27% (Hong Kong), and 15-45% (South Asia, South-East Asia, Korea, Japan and Taiwan). This Review presents emerging data on genetic polymorphisms that predispose Asian people to NAFLD, NASH and cirrhosis, and discusses the clinical and pathological outcomes of these disorders. NAFLD is unlikely to be less severe in Asians than in other populations, but the associated obesity and diabetes pandemics have occurred more recently in Asia than in Europe and the USA, and occur with reduced degrees of adiposity. Cases of cryptogenic cirrhosis and hepatocellular carcinoma have also been attributed to NAFLD. Public health efforts to curb over-nutrition and insulin resistance are needed to prevent and/or reverse NAFLD, as well as its adverse health outcomes of type 2 diabetes, cardiovascular events, cirrhosis and liver cancer.
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Affiliation(s)
- Geoffrey C Farrell
- ANU Medical School, Australian National University and Gastroenterology and Hepatology Unit, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia.
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Santoro N, Feldstein AE, Enoksson E, Pierpont B, Kursawe R, Kim G, Caprio S. The association between hepatic fat content and liver injury in obese children and adolescents: effects of ethnicity, insulin resistance, and common gene variants. Diabetes Care 2013; 36:1353-60. [PMID: 23275357 PMCID: PMC3631865 DOI: 10.2337/dc12-1791] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are highly prevalent in obese youth. Herein, we aimed to study the association between hepatic fat accumulation as assessed by magnetic resonance imaging and circulating levels of cytokeratin-18 (CK-18) fragments, a robust NASH biomarker, and to explore the impact on this association of ethnicity, insulin resistance, and single nucleotide polymorphisms (SNPs) associated with steatosis (rs738409 in the PNPLA3, rs1260326 in the GCKR) or NASH severity (rs2645424 in the FDFT1). RESEARCH DESIGN AND METHODS Two-hundred twenty-nine obese youths (87 Caucasians, 61 African Americans, and 81 Hispanics; mean age, 12.8 ± 2.9 years; mean BMI, 31.4 ± 7.4) underwent magnetic resonance imaging, oral glucose tolerance test, and CK-18 levels measurement; 12 subjects underwent liver biopsy. RESULTS African Americans showed lower CK-18 levels than Hispanics (P < 0.001) and Caucasians (P = 0.004). Hepatic fat content (HFF%) and whole body insulin sensitivity index (WBISI) modulated CK-18 levels in Caucasians and Hispanics (P = 0.02 and P = 0.011), but not in African Americans; in fact, CK-18 was associated with HFF% and WBISI in Caucasians (P = 0.0018 and P < 0.0001) and Hispanics (P < 0.0001 and P = 0.02), but not in African Americans (both P = 0.5). The PNPLA3 SNP showed association in Caucasians (P = 0.02) and Hispanics (P = 0.05), and FDFT1 SNP showed an association in Caucasians (P = 0.05) and Hispanics (P = 0.02), with the same trend in African Americans (P = 0.07). CONCLUSIONS African Americans have lower levels of CK-18 than Caucasians and Hispanics irrespective of HFF% and insulin resistance. Moreover, SNPs in the PNPLA3 and FDFT1 may drive the individual predisposition to development of hepatic injury.
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Affiliation(s)
- Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
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Okada Y, Yamaguchi K, Nakajima T, Nishikawa T, Jo M, Mitsumoto Y, Kimura H, Nishimura T, Tochiki N, Yasui K, Mitsuyoshi H, Minami M, Kagawa K, Okanoue T, Itoh Y. Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats. Liver Int 2013; 33:301-11. [PMID: 23295058 DOI: 10.1111/liv.12033] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Accepted: 10/16/2012] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model. METHODS Eight-week-old male Sprague-Dawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated. RESULTS As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-α and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-β, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or α-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored. CONCLUSIONS These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal β-oxidation in this rat HFHC model.
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Affiliation(s)
- Yoshihisa Okada
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Brockman DA, Chen X, Gallaher DD. Consumption of a high β-glucan barley flour improves glucose control and fatty liver and increases muscle acylcarnitines in the Zucker diabetic fatty rat. Eur J Nutr 2012. [PMID: 23229409 DOI: 10.1007/s00394‐012‐0478‐2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
PURPOSE The soluble fiber β-glucan, a natural component of barley, has been shown to lower the postprandial glucose response and is thought to improve insulin resistance. METHODS This study examined the effect of chronic consumption of the high β-glucan barley flour on glucose control, liver lipids and markers of muscle fatty acid oxidation in the Zucker diabetic fatty (ZDF) rat. Two groups of ZDF rats were fed diets containing either 6% β-glucan in the form of barley flour or cellulose as a control for 6 weeks. A group of Zucker lean rats served as a negative control. RESULTS The barley flour group had an increased small intestinal contents viscosity compared to the obese control group. After 6 weeks, the barley flour group had reduced glycated hemoglobin, lower relative kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Fasting plasma adiponectin levels increased in the barley flour group and were not different than the lean control group. ZDF rats on the barley flour diet had lower relative epididymal fat pad weights than the obese control and a greater food efficiency ratio. The barley flour group also had reduced liver weights and a decreased concentration of liver lipids. The barley flour group had significantly higher concentrations of muscle acylcarnitines, a metabolite generated during fatty acid oxidation. CONCLUSION These results show that chronic consumption of β-glucans can improve glucose control and decrease fatty liver in a model of diabetes with obesity.
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Affiliation(s)
- David A Brockman
- Department of Food Science and Nutrition, University of Minnesota-Twin Cities, 1334 Eckles Avenue, St. Paul, MN, 55108-1038, USA
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Consumption of a high β-glucan barley flour improves glucose control and fatty liver and increases muscle acylcarnitines in the Zucker diabetic fatty rat. Eur J Nutr 2012; 52:1743-53. [PMID: 23229409 DOI: 10.1007/s00394-012-0478-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 11/27/2012] [Indexed: 01/21/2023]
Abstract
PURPOSE The soluble fiber β-glucan, a natural component of barley, has been shown to lower the postprandial glucose response and is thought to improve insulin resistance. METHODS This study examined the effect of chronic consumption of the high β-glucan barley flour on glucose control, liver lipids and markers of muscle fatty acid oxidation in the Zucker diabetic fatty (ZDF) rat. Two groups of ZDF rats were fed diets containing either 6% β-glucan in the form of barley flour or cellulose as a control for 6 weeks. A group of Zucker lean rats served as a negative control. RESULTS The barley flour group had an increased small intestinal contents viscosity compared to the obese control group. After 6 weeks, the barley flour group had reduced glycated hemoglobin, lower relative kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Fasting plasma adiponectin levels increased in the barley flour group and were not different than the lean control group. ZDF rats on the barley flour diet had lower relative epididymal fat pad weights than the obese control and a greater food efficiency ratio. The barley flour group also had reduced liver weights and a decreased concentration of liver lipids. The barley flour group had significantly higher concentrations of muscle acylcarnitines, a metabolite generated during fatty acid oxidation. CONCLUSION These results show that chronic consumption of β-glucans can improve glucose control and decrease fatty liver in a model of diabetes with obesity.
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