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1
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Liu R, Jin Y, Liu B, Zhang Q, Li X, Cai D, Tian L, Jiang X, Zhang W, Sun J, Bai W. Untargeted Lipidomics Revealed the Protective Effects of Cyanidin-3- O-glucoside on Bisphenol A-Induced Liver Lipid Metabolism Disorder in Rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:1077-1090. [PMID: 36597173 DOI: 10.1021/acs.jafc.2c06849] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Bisphenol A (BPA) is an estrogenic endocrine disruptor that induces metabolic disorders. Cyanidin-3-O-glucoside (C3G) has multiple functional activities and is the most abundant anthocyanin belonging to the flavonoid subgroup. This study aimed to investigate the protective effect of C3G on BPA-induced liver lipid metabolism disorder and explore its mechanism via lipidomics analysis. The results showed that C3G supplementation significantly ameliorated the serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triacylglycerols (TG), and alanine and aspartate aminotransferase (ALT and AST). Furthermore, liver lipidomics indicated that C3G effectively facilitated the recovery of differential lipid metabolites, including TGs, phosphatidylethanolamines, phosphatidylcholines, lysophosphatidylcholines, phosphatidylinositol, cholesteryl esters, and phosphatidylserine, and reversed the levels of hepatic lipid synthesis-related genes. Our results suggest that C3G has an effective regulatory effect on BPA-induced disorders of lipid metabolism.
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Affiliation(s)
- Ruijing Liu
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
- Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Yulong Jin
- Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Boping Liu
- Key Laboratory for Bio-Based Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Qing Zhang
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Xusheng Li
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Dongbao Cai
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Lingmin Tian
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Xinwei Jiang
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Wenbao Zhang
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
| | - Jianxia Sun
- School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, P. R. China
| | - Weibin Bai
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular Rapid Detection, Jinan University, Guangzhou 510632, P. R. China
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Chakraborty S, Dissanayake M, Godwin J, Wang X, Bhandari RK. Ancestral BPA exposure caused defects in the liver of medaka for four generations. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 856:159067. [PMID: 36174697 PMCID: PMC10593180 DOI: 10.1016/j.scitotenv.2022.159067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/01/2022] [Accepted: 09/23/2022] [Indexed: 06/16/2023]
Abstract
Environmental chemicals can induce liver defects in experimental animals due to their direct and acute exposure. It is not clear whether environmental chemical exposures result in the transgenerational passage of liver defects in subsequent generations living in an uncontaminated environment. Bisphenol A (BPA), a plasticizer chemical, has been ubiquitous in the environment in the recent decade. Every organism is exposed to this chemical at some point during its lifetime. Literature suggests that direct BPA exposure can result in several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Despite the phasing out of BPA from several consumer goods, it is unclear whether ancestral BPA exposure causes liver health problems in the unexposed future generations. Here, we demonstrate an advanced stage of NAFLD in the grandchildren (F2 generation) of medaka fish (Oryzias latipes) due to embryonic BPA exposure in the grandparental generation (F0), which persists for five generations (F4) even in the absence of BPA. The severity of transgenerational NAFLD phenotype included steatosis together with perisinusoidal fibrosis and apoptosis of hepatocytes. Adult females developed more severe histopathological conditions in the liver than males. Genes encoding enzymes involved in lipolytic pathways were significantly decreased. The present results suggest that ancestral BPA exposure can result in transgenerational metabolic diseases that can persist for five generations and that the NAFLD trait is sexually dimorphic. Given that ancestral BPA exposure can lead to altered metabolic health outcomes in the subsequent unexposed generations, the development of the methods and strategies to mitigate the transgenerational onset of metabolic diseases seem imperative to protect future generations.
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Affiliation(s)
- Sourav Chakraborty
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Manthi Dissanayake
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Julia Godwin
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Xuegeng Wang
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA; Institute of Modern Aquaculture Science and Engineering, College of Life Sciences, South China Normal University, Guangzhou 510631, PR China
| | - Ramji Kumar Bhandari
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA.
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Singh SP, Anirvan P, Khandelwal R, Satapathy SK. Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille? J Clin Transl Hepatol 2021; 9:931-938. [PMID: 34966656 PMCID: PMC8666378 DOI: 10.14218/jcth.2021.00174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/21/2021] [Accepted: 07/18/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects about a quarter of the world's population and poses a major health and economic burden globally. Recently, there have been hasty attempts to rename NAFLD to metabolic-associated fatty liver disease (MAFLD) despite the fact that there is no scientific rationale for this. Quest for a "positive criterion" to diagnose the disease and destigmatizing the disease have been the main reasons put forth for the name change. A close scrutiny of the pathogenesis of NAFLD would make it clear that NAFLD is a heterogeneous disorder, involving different pathogenic mechanisms of which metabolic dysfunction-driven hepatic steatosis is only one. Replacing NAFLD with MAFLD would neither enhance the legitimacy of clinical practice and clinical trials, nor improve clinical care or move NAFLD research forward. Rather than changing the nomenclature without a strong scientific backing to support such a change, efforts should be directed at understanding NAFLD pathogenesis across diverse populations and ethnicities which could potentially help develop newer therapeutic options.
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Affiliation(s)
- Shivaram P. Singh
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
- Correspondence to: Shivaram P Singh, Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha 753007, India. ORCID: https://orcid.org/0000-0002-8197-2674. Tel: +91-9437578857, Fax: +91-671-2433865, E-mail:
| | - Prajna Anirvan
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Reshu Khandelwal
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Impact of PPAR-Alpha Polymorphisms-The Case of Metabolic Disorders and Atherosclerosis. Int J Mol Sci 2019; 20:ijms20184378. [PMID: 31489930 PMCID: PMC6770475 DOI: 10.3390/ijms20184378] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/01/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.
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Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, De Bosscher K. Molecular Actions of PPARα in Lipid Metabolism and Inflammation. Endocr Rev 2018; 39:760-802. [PMID: 30020428 DOI: 10.1210/er.2018-00064] [Citation(s) in RCA: 502] [Impact Index Per Article: 71.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 07/10/2018] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
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Affiliation(s)
- Nadia Bougarne
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Basiel Weyers
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Sofie J Desmet
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Julie Deckers
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation, VIB Center for Inflammation Research, Ghent (Zwijnaarde), Belgium
| | - David W Ray
- Division of Metabolism and Endocrinology, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Bart Staels
- Université de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
- INSERM, U1011, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
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The genetic backgrounds in nonalcoholic fatty liver disease. Clin J Gastroenterol 2018; 11:97-102. [PMID: 29492830 DOI: 10.1007/s12328-018-0841-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 02/22/2018] [Indexed: 12/21/2022]
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Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 2017; 111:173-185. [PMID: 28109892 DOI: 10.1016/j.freeradbiomed.2017.01.023] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/11/2017] [Accepted: 01/15/2017] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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Affiliation(s)
- Francesco Bellanti
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Villani
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Antonio Facciorusso
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.
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Umano GR, Martino M, Santoro N. The Association between Pediatric NAFLD and Common Genetic Variants. CHILDREN-BASEL 2017. [PMID: 28629152 PMCID: PMC5483624 DOI: 10.3390/children4060049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease.
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Affiliation(s)
- Giuseppina Rosaria Umano
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento della Donna, del Bambino, di Vhirurgia Generale e Specialistica, Universita' della Campania Luigi Vanvitelli, 80138, Napoli, Italy.
| | - Mariangela Martino
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
| | - Nicola Santoro
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
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10
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Wang C, Gong J, Wu H. Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease. Biomed Rep 2017; 7:95-104. [PMID: 28804621 DOI: 10.3892/br.2017.926] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, the morbidity of which closely correlates with diversity of ethnicity, minority, family and location. Its histology spans from simple steatosis, to nonalcoholic steatohepatitis, which ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma. The accelerating prevalence of NAFLD is due to an incremental incidence of metabolic syndrome that is distinguished by dyslipidemia, glucose impairment, obesity, excessive oxidative stress and adipocytokine impairment. Additionally, the pathogenesis of NAFLD is thought to be a multifactorial and complicated disease associated with lifestyle habits, nutritional factors and genetics. However, the pathogenesis and underlying mechanism in the development of NAFLD caused by genetics remains unclear. People have been increasingly emphasizing on the relationship between NAFLD and gene polymorphisms in recent years, with the aim of having a comprehensive elucidation of associated gene polymorphisms influencing the pathogenesis of the disease. In the current article, the authors attempted to critically summarize the most recently identified gene polymorphisms from the facets of glucose metabolism, fatty acid metabolism, oxidative stress and related cytokines in NAFLD that contribute to promoting the progression of the disease.
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Affiliation(s)
- Chun Wang
- Department of General Surgery, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing 402161, P.R. China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hao Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
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Kubo H, Hoshi M, Matsumoto T, Irie M, Oura S, Tsutsumi H, Hata Y, Yamamoto Y, Saito K. Sake lees extract improves hepatic lipid accumulation in high fat diet-fed mice. Lipids Health Dis 2017; 16:106. [PMID: 28578672 PMCID: PMC5457550 DOI: 10.1186/s12944-017-0501-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 05/25/2017] [Indexed: 02/06/2023] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide as one of the leading causes of chronic liver disease. Sake lees (SL) are secondary products of sake manufacturing and are considered to have beneficial effects on human health. To investigate these effects, we used high fat diet (HFD)-fed mice treated with or without the SL extract. Method Mice were the HFD ad libitum for 8 weeks and were administered 500 μL of distilled water with or without the SL extract (350 mg/mL) by a feeding needle daily for the last 4 weeks. Food intake, body weight, and liver weight were measured. Triacylglycerol content and the mRNA and protein expression levels of various lipid and glucose metabolism-related genes were determined in liver tissues. The levels of triglyceride, free fatty acids, glucose, insulin, and liver cell damage markers were determined in serum. Fatty acid-induced lipid accumulation in HepG2 cells was assessed in the presence or absence of the SL extract. Results Mice fed a HFD and treated with the SL extract demonstrated a significant reduction in hepatic lipid accumulation and mRNA and protein levels of peroxidome proliferator-activated receptor γ (PPARγ), PPARα, CD36, and phosphoenolpyruvate carboxykinase 1 in the liver, while the SL extract did not affect body weight and food intake. Moreover, insulin resistance and hepatic inflammation in HFD-fed mice improved after administration of the SL extract. In HepG2 cells, the SL extract suppressed fatty acid-induced intracellular lipid accumulation. Conclusions These findings suggest that treatment with the SL extract could potentially reduce the risk of NAFLD development, and that the SL extract may be clinically useful for the treatment of NAFLD.
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Affiliation(s)
- Hisako Kubo
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Masato Hoshi
- Department of Biochemical and Analytical Sciences, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Takuya Matsumoto
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Motoko Irie
- Research Institute, Gekkeikan Sake Co. Ltd., 247 Minamihamcho, Fushimi, Kyoto, 612-8385, Japan
| | - Shin Oura
- Research Institute, Gekkeikan Sake Co. Ltd., 247 Minamihamcho, Fushimi, Kyoto, 612-8385, Japan
| | - Hiroko Tsutsumi
- Research Institute, Gekkeikan Sake Co. Ltd., 247 Minamihamcho, Fushimi, Kyoto, 612-8385, Japan
| | - Yoji Hata
- Research Institute, Gekkeikan Sake Co. Ltd., 247 Minamihamcho, Fushimi, Kyoto, 612-8385, Japan
| | - Yasuko Yamamoto
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan
| | - Kuniaki Saito
- Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. .,Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi, 470-1192, Japan.
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12
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Miyaaki H, Nakao K. Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease. Clin J Gastroenterol 2017; 10:201-207. [PMID: 28290069 DOI: 10.1007/s12328-017-0732-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 03/02/2017] [Indexed: 12/16/2022]
Abstract
Because of recent advances in genetic research such as genome-wide association studies, the underlying genetic mechanisms of nonalcoholic fatty liver disease (NAFLD) pathophysiology have been elucidated. Here, we present a review of the current literature on the impact of genetic polymorphisms in patients with NAFLD. These genetic polymorphisms, which regulate lipid metabolism, glucose metabolism, and the renin-angiotensin system, are involved in NAFLD onset, steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). Among these genetic polymorphisms, many studies and meta-analyses have demonstrated that position 148 (rs738409 C/G) of the patatin-like phospholipase domain-containing protein (PNPLA3) is a genetic factor associated with NAFLD pathophysiological features, such as hepatic fat level, hepatic inflammation, fibrosis, and HCC. However, the impact of genetic polymorphisms on NAFLD pathophysiology appears to differ among ethnic groups. Therefore, further studies with larger sample sizes are needed for each ethnic group.
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Affiliation(s)
- Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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13
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Severson TJ, Besur S, Bonkovsky HL. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review. World J Gastroenterol 2016; 22:6742-6756. [PMID: 27547017 PMCID: PMC4970479 DOI: 10.3748/wjg.v22.i29.6742] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/28/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review.
METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur.
RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine.
CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.
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Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150:1728-1744.e7. [PMID: 26873399 DOI: 10.1053/j.gastro.2016.01.037] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 01/17/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023]
Abstract
Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
| | - Devanshi Seth
- Centenary Institute of Cancer Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Drug Health Services, Royal Prince Alfred Hospital, Camperdown, Australia; Central Clinical School, The University of Sydney, Camperdown, Australia
| | - Christopher P Day
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom
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Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther 2016; 33:291-319. [PMID: 26921205 DOI: 10.1007/s12325-016-0306-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
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Affiliation(s)
| | - Fabio Nascimbeni
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
- University of Modena and Reggio Emilia, Modena, Italy
| | - Dante Romagnoli
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
| | | | - Amedeo Lonardo
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.
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Youssef J, Badr M. Peroxisome Proliferator-Activated Receptors Features, Functions, and Future. NUCLEAR RECEPTOR RESEARCH 2015. [DOI: 10.11131/2015/101188] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Ramos-Lopez O, Martinez-Lopez E, Roman S, Fierro NA, Panduro A. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21:11552-11566. [PMID: 26556986 PMCID: PMC4631960 DOI: 10.3748/wjg.v21.i41.11552] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Ling Q, Xu X, Wang K, Wang C, Xiang P, Zhang X, Zhuang R, Xie H, Zheng S. Donor PPARα Gene Polymorphisms Influence the Susceptibility to Glucose and Lipid Disorders in Liver Transplant Recipients: A Strobe-Compliant Observational Study. Medicine (Baltimore) 2015; 94:e1421. [PMID: 26334901 PMCID: PMC4616503 DOI: 10.1097/md.0000000000001421] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of glucose and lipid metabolism, and is predominantly expressed in the liver. We aimed to evaluate the effect of donor hepatic PPARα gene polymorphisms on the development of metabolic disorders following liver transplantation (LT).A total of 176 patients undergoing primary LT were included in this Review Board-approved study. Genomic DNA was extracted from fresh frozen donor liver tissues (biopsy specimens for pathological testing at surgery). Eight single nucleotide polymorphisms in the PPARα gene were chosen from either the HapMap CHB database or previous reports.The distribution of metabolic disorders differed significantly between the wild-type and variant genotypes of both the rs5767743 and rs5767700 loci (P < 0.05 for all). After an adjustment for other factors (body mass index and tacrolimus blood concentration), the rs5767743 genetic variant was found to be an independent protective factor (P = 0.005, odds ratio = 0.416 per C allele, 95% confidence interval = 0.225-0.768). When compared with the wild-type genotype, the variant genotypes rs5767743 and rs5767700 correlated with significantly increased PPARα and CYP3A4 mRNA expression and lower tacrolimus trough concentration/dose ratios (P < 0.05 for all).Donor PPARα gene polymorphisms influence the susceptibility to metabolic disorders following LT and may also be associated with a fasten tacrolimus metabolism because of elevated CYP3A4 expression.
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Affiliation(s)
- Qi Ling
- From the Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (QL, XX, KW,CW, PX, XZ, RZ, HX, SZ); and Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, China (QL, XX, HX, SZ)
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Edelman D, Kalia H, Delio M, Alani M, Krishnamurthy K, Abd M, Auton A, Wang T, Wolkoff AW, Morrow BE. Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population. Mol Genet Genomic Med 2015; 3:558-69. [PMID: 26740948 PMCID: PMC4694126 DOI: 10.1002/mgg3.168] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/07/2015] [Accepted: 07/09/2015] [Indexed: 12/18/2022] Open
Abstract
We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean–Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy‐proven NAFLD, 24 ethnically matched non‐NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome‐wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted.
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Affiliation(s)
- Deborah Edelman
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Harmit Kalia
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Maria Delio
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
| | - Mustafa Alani
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Karthik Krishnamurthy
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Mortadha Abd
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Adam Auton
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Tao Wang
- Department of Epidemiology & Population HealthAlbert Einstein College of MedicineBronxNew York10461
| | - Allan W. Wolkoff
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
| | - Bernice E. Morrow
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
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Association of adiponectin gene polymorphism with nonalcoholic fatty liver disease in Taiwanese patients with type 2 diabetes. PLoS One 2015; 10:e0127521. [PMID: 26042596 PMCID: PMC4456357 DOI: 10.1371/journal.pone.0127521] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/15/2015] [Indexed: 12/25/2022] Open
Abstract
Objective Patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) have a higher prevalence of cardiovascular diseases. In this study we investigated the frequency of single nucleotide polymorphisms (SNPs) of several candidate genes associated with NAFLD in Taiwanese patients with type 2 diabetes mellitus (DM) and NAFLD and in those with DM but without fatty liver disease. Methods We enrolled 350 patients with type 2 DM and NAFLD and 209 patients with DM but without NAFLD. Body mass index (BMI), % body fat (% BF), glycated hemoglobin (HbA1c), high molecular weight (HMW) isoform of adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured. Thirteen SNPs in 5 genes (adiponectin, leptin, peroxisome proliferator-activated receptor alpha, adiponutrin/patatin-like phospholipase domain-containing protein 3 and peroxisome proliferator-activated receptor γ co-activator 1α ) were measured. Results Only adiponectin rs266729 polymorphism was associated with susceptibility to NAFLD (p = 0.001). Subgroup analysis revealed that the proportion of subjects with homozygous genotype GG was higher in patients with NAFLD (31%) than in controls (11%) and that the proportions of heterozygous CG and homozygous CC were higher in controls (37% and 52%, respectively) than in patients with NAFLD (33% and 36%, respectively). Patients with NAFLD carrying the GG genotype of rs266729 showed significantly lower serum HMW adiponectin levels than patients carrying the GC or CC genotype (3.75±0.37 vs. 3.99±0.66 vs. 4.79±0.58 μg/ml, p< 0.001). Body fat and serum HMW adiponectin levels were the strongest predictors of developing NAFLD (p < 0.001 and 0.004, respectively). Conclusions In patients with type 2 diabetes gene polymorphism of adiponectin rs266729 is associated with risk of NAFLD. G allele of rs266729 is associated with hypoadiponectinemia. Low serum adiponectin level may precipitate liver steatosis in patients with type 2 diabetes.
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Sharma M, Mitnala S, Vishnubhotla RK, Mukherjee R, Reddy DN, Rao PN. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis. J Clin Exp Hepatol 2015; 5:147-58. [PMID: 26155043 PMCID: PMC4491606 DOI: 10.1016/j.jceh.2015.02.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 02/09/2015] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.
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Key Words
- AGE, Advanced glycation end products
- ALT, Alanine aminotransferase
- AMPK, AMP-activated protein Kinase
- APPL1 and 2, Adaptor protein 1 and 2
- ATP, Adenosine tri-phosphatase
- BMI, Basal Metabolic Index
- CD, Cluster of differentiation
- COL13A1, Collagen, type XIII, alpha 1
- DAMP, Damage assocauted molecular pattern molecules
- EFCAB4B, EF-hand calcium binding domain 4B
- FA, Fatty acid
- FDFT1, Farnesyl-diphosphate farnesyltransferase 1
- FFA, Free fatty acid
- GCKR, Glucokinase regulatory protein
- GLUT 5, Glucose transporter type 5
- GWAS, Genome wide association studies
- HDL, High density lipoprotein
- HMGB1, High-mobility group protein B1
- HOMA-IR, Homoestatic model assessment-insulin resistance
- HSC, Hepatic Stellate Cells
- Hh, Hedgehog
- IL6, Interleukin 6
- IR, Insulin Resistance
- KC, Kupffer Cells
- LPS, Lipopolysacharrides
- LYPLAL1, Lypophospholipase like 1
- MCP, Monocyte chemotactic protein
- NAD, Nicotinamide adenine dinucleotide
- NAFL, Nonalcoholic fatty liver
- NAFLD, Nonalcoholic fatty liver disease
- NASH, Nonalcoholic steatohepatitis
- NCAN, Neurocan gene
- NF-KB, Nuclear Factor Kappa B
- NK, Natural Killer
- NKL, Natural Killer T cells
- NLR, NOD like receptor
- NNMT, Nicotinamide N-methyltransferase gene
- OXLAM, Oxidized linolenic acid metabolite
- PAMP, Pathogen-associated Molecular pattern
- PARVB, Beta Parvin Gene
- PDGF, Platelet-derived growth factor
- PNPLA3
- PNPLA3, Patatin-like phospholipase domain-containing protein 3
- PPAR-α, Peroxisome proliferator activated receptor alpha
- PPP1R3B, Protein phosphatase 1 R3B
- PUFA, Poly unsaturated fatty acid
- PZP, Pregnancy-zone protein
- ROS, Reactive oxygen species
- SAMM, Sorting and assembly machinery component
- SCAP, SREBP cleavage-activating protein
- SFA, Saturated fatty acid
- SNP, Single nucleotide polymorphism
- SOCS3, Suppressor of cytokine signaling 3
- SOD2, Superoxide dismutase 2 gene
- SREBP-1C, Sterol regulatory Element—Binding Protein 1-C gene
- TLR, Toll like receptor
- TNF α, Tumor necrosis factor Alpha
- UCP3, Uncoupling protein 3 gene
- adiponectin
- cytokines
- gut microbiota
- lipotoxicity
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Affiliation(s)
- Mithun Sharma
- Department of Hepatology and Nutrition, Asian Institute of Gastroenterology, Hyderabad, Telangana, India,Address for correspondence: Mithun Sharma, Consultant Hepatologist, Asian Institute of Gastroenterology, 6-3-661, Red Rose Café Lane, Somajigudda, Hyderabad 500082, India. Tel.: +91 8790622655.
| | - Shasikala Mitnala
- Research Labs, Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Ravi K. Vishnubhotla
- Department of Genetics, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rathin Mukherjee
- Department of Molecular Biology, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Duvvur N. Reddy
- Department of Gastroenterology, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Padaki N. Rao
- Department of Hepatology and Nutrition, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
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Dong C, Zhou H, Shen C, Yu LG, Ding Y, Zhang YH, Guo ZR. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome. World J Diabetes 2015; 6:654-661. [PMID: 25987964 PMCID: PMC4434087 DOI: 10.4239/wjd.v6.i4.654] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/27/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.
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Peroxisome proliferator-activated receptor alpha1 in yellow catfish Pelteobagrus fulvidraco: Molecular characterization, mRNA tissue expression and transcriptional regulation by insulin in vivo and in vitro. Comp Biochem Physiol B Biochem Mol Biol 2015; 183:58-66. [DOI: 10.1016/j.cbpb.2015.01.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 01/22/2015] [Accepted: 01/23/2015] [Indexed: 11/18/2022]
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Mazzoccoli G, Vinciguerra M, Oben J, Tarquini R, De Cosmo S. Non-alcoholic fatty liver disease: the role of nuclear receptors and circadian rhythmicity. Liver Int 2014; 34:1133-52. [PMID: 24649929 DOI: 10.1111/liv.12534] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 03/16/2014] [Indexed: 12/22/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the accumulation of triglycerides in the hepatocytes in the absence of excess alcohol intake, and is caused by an imbalance between hepatic synthesis and breakdown of fats, as well as fatty acid storage and disposal. Liver metabolic pathways are driven by circadian biological clocks, and hepatic health is maintained by proper timing of circadian patterns of metabolic gene expression with the alternation of anabolic processes corresponding to feeding/activity during wake times, and catabolic processes characterizing fasting/resting during sleep. A number of nuclear receptors in the liver are expressed rhythmically, bind hormones and metabolites, sense energy flux and expenditure, and connect the metabolic pathways to the molecular clockwork throughout the 24-h day. In this review, we describe the role played by the nuclear receptors in the genesis of NAFLD in relationship with the circadian clock circuitry.
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Affiliation(s)
- Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
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Lu Y, Liu X, Jiao Y, Xiong X, Wang E, Wang X, Zhang Z, Zhang H, Pan L, Guan Y, Cai D, Ning G, Li X. Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα. J Clin Invest 2014; 124:3501-13. [PMID: 25003192 DOI: 10.1172/jci74438] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 05/22/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.
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Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2014; 19:5219-38. [PMID: 23394097 PMCID: PMC3850262 DOI: 10.2174/13816128113199990381] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 02/01/2013] [Indexed: 02/07/2023]
Abstract
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
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Affiliation(s)
- Paola Dongiovanni
- Department of Pathophysiology and Transplantation, section Internal Medicine, Università degli Studi Milano, UO Medicina Interna1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Mehta R, Birerdinc A, Younossi ZM. Host genetic variants in obesity-related nonalcoholic fatty liver disease. Clin Liver Dis 2014; 18:249-67. [PMID: 24274878 DOI: 10.1016/j.cld.2013.09.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex disease. The considerable variability in the natural history of the disease suggests an important role for genetic variants in the disease development and progression. There is evidence based on genome-wide association studies and/or candidate gene studies that genetic polymorphisms underlying insulin signaling, lipid metabolism, oxidative stress, fibrogenesis, and inflammation can predispose individuals to NAFLD. This review highlights some of the genetic variants in NAFLD.
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Affiliation(s)
- Rohini Mehta
- Betty and Guy Beatty Center for Integrated Research, Center for Liver Disease, Inova Health System, Claude Moore Building, 3300 Gallows Road, Falls Church, VA 22042, USA
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Serviddio G, Bellanti F, Vendemiale G. Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radic Biol Med 2013; 65:952-968. [PMID: 23994574 DOI: 10.1016/j.freeradbiomed.2013.08.174] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 08/20/2013] [Accepted: 08/20/2013] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
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Affiliation(s)
- Gaetano Serviddio
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
| | - Francesco Bellanti
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Domenici FA, Brochado MJF, Martinelli ADLC, Zucoloto S, da Cunha SFDC, Vannucchi H. Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients. Gene 2013; 529:326-31. [PMID: 23891824 DOI: 10.1016/j.gene.2013.06.091] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Revised: 06/11/2013] [Accepted: 06/27/2013] [Indexed: 01/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD. METHODS One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP. CONCLUSIONS We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.
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Affiliation(s)
- Fernanda Aparecida Domenici
- Clinical Nutrition Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Pathology and Legal Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
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31
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Conn CA, Vaughan RA, Garver WS. Nutritional Genetics and Energy Metabolism in Human Obesity. Curr Nutr Rep 2013. [DOI: 10.1007/s13668-013-0046-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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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: 349] [Impact Index Per Article: 29.1] [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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Naik A, Košir R, Rozman D. Genomic aspects of NAFLD pathogenesis. Genomics 2013; 102:84-95. [PMID: 23545492 DOI: 10.1016/j.ygeno.2013.03.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/19/2013] [Accepted: 03/22/2013] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most predominant liver disease worldwide and hepatic manifestation of the metabolic syndrome. Its histology spectrum ranges from steatosis, to steatohepatitis (NASH) that can further progress to cirrhosis and hepatocellular carcinoma (HCC). The increasing incidence of NAFLD has contributed to rising numbers of HCC occurrences. NAFLD progression is governed by genetic susceptibility, environmental factors, lifestyle and features of the metabolic syndrome, many of which overlap with HCC. Gene expression profiling and genome wide association studies have identified novel disease pathways and polymorphisms in genes that may be potential biomarkers of NAFLD progression. However, the multifactorial nature of NAFLD and the limited number of sufficiently powered studies are among the current limitations for validated biomarkers of clinical utility. Further studies incorporating the links between circadian regulation and hepatic metabolism might represent an additional direction in the search for predictive biomarkers of liver disease progression and treatment outcomes.
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Affiliation(s)
- Adviti Naik
- Faculty of Computer Sciences and Informatics, Tržaška Cesta 25, Ljubljana 1000, University of Ljubljana, Slovenia
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Dongiovanni P, Valenti L. Peroxisome proliferator-activated receptor genetic polymorphisms and nonalcoholic Fatty liver disease: any role in disease susceptibility? PPAR Res 2013; 2013:452061. [PMID: 23431284 PMCID: PMC3575610 DOI: 10.1155/2013/452061] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 11/13/2012] [Accepted: 11/20/2012] [Indexed: 12/21/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.
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Affiliation(s)
- Paola Dongiovanni
- Section of Internal Medicine, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milano, Italy
| | - Luca Valenti
- Section of Internal Medicine, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milano, Italy
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Naik A, Belič A, Zanger UM, Rozman D. Molecular Interactions between NAFLD and Xenobiotic Metabolism. Front Genet 2013; 4:2. [PMID: 23346097 PMCID: PMC3550596 DOI: 10.3389/fgene.2013.00002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 01/03/2013] [Indexed: 01/01/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD.
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Affiliation(s)
- Adviti Naik
- Faculty of Computer Sciences and Informatics, University of Ljubljana Ljubljana, Slovenia
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Videla LA, Pettinelli P. Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity. PPAR Res 2012; 2012:107434. [PMID: 23304111 PMCID: PMC3526338 DOI: 10.1155/2012/107434] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 11/06/2012] [Indexed: 12/22/2022] Open
Abstract
Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-α downregulation with parallel PPAR-γ and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.
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Affiliation(s)
- Luis A. Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago 7, Chile
| | - Paulina Pettinelli
- Ciencias de la Salud, Nutrición y Dietética, Facultad de Medicina, Pontificia Universidad Católica de Chile, 7820436 Santiago, Chile
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Peng XE, Wu YL, Lin SW, Lu QQ, Hu ZJ, Lin X. Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population. PLoS One 2012; 7:e50256. [PMID: 23226254 PMCID: PMC3511464 DOI: 10.1371/journal.pone.0050256] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 10/17/2012] [Indexed: 02/06/2023] Open
Abstract
We investigated the possible association between genetic variants in the Patatin like phospholipase-3 (PNPLA3) gene and nonalcoholic fatty liver disease (NAFLD) in a Han Chinese population. We evaluated twelve tagging single-nucleotide polymorphisms (tSNPs) of the PNPLA3 gene in a frequency matched case–control study from Fuzhou city of China (553 cases, 553 controls). In the multivariate logistic regression analysis, the rs738409 GG or GC, and rs139051 TT genotypes were found to be associated with increased risk of NAFLD, and a significant trend of increased risk with increasing numbers of risk genotype was observed in the cumulative effect analysis of these single nucleotide polymorphisms. Furthermore, haplotype association analysis showed that, compared with the most common haplotype, the CAAGAATGCGTG and CGAAGGTGTCCG haplotypes conferred a statistically significant increased risk for NAFLD, while the CGGGAACCCGCG haplotype decreased the risk of NAFLD. Moreover, rs738409 C>G appeared to have a multiplicative joint effect with tea drinking (P<0.005) and an additive joint effect with obesity (Interaction contrast ratio (ICR) = 2.31, 95% CI: 0.7–8.86), hypertriglyceridemia (ICR = 3.07, 95% CI: 0.98–5.09) or hypertension (ICR = 1.74, 95% CI: 0.52–3.12). Our data suggests that PNPLA3 genetic polymorphisms might influence the susceptibility to NAFLD development independently or jointly in Han Chinese.
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Affiliation(s)
- Xian-E Peng
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center of Molecular Medicine, Fujian Medical University, Fuzhou, China
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yun-Li Wu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center of Molecular Medicine, Fujian Medical University, Fuzhou, China
- Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Shao-Wei Lin
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Qing-Qing Lu
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, China
| | - Zhi-Jian Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center of Molecular Medicine, Fujian Medical University, Fuzhou, China
- Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
- * E-mail:
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Peyrou M, Ramadori P, Bourgoin L, Foti M. PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs. PPAR Res 2012; 2012:757803. [PMID: 23024649 PMCID: PMC3449131 DOI: 10.1155/2012/757803] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 06/27/2012] [Indexed: 12/19/2022] Open
Abstract
Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.
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Affiliation(s)
- Marion Peyrou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Pierluigi Ramadori
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Centre Médical Universiatire (CMU), 1206 Geneva, Switzerland
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Adams LA, Marsh JA, Ayonrinde OT, Olynyk JK, Ang WQ, Beilin LJ, Mori T, Palmer LJ, Oddy WW, Lye SJ, Pennell CE. Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity. J Gastroenterol Hepatol 2012; 27:1520-7. [PMID: 22414273 DOI: 10.1111/j.1440-1746.2012.07120.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Environmental factors including excessive caloric intake lead to disordered lipid metabolism and fatty liver disease (FLD). However, FLD demonstrates heritability suggesting genetic factors are also important. We aimed to use a candidate gene approach to examine the association between FLD and single nucleotide polymorphisms (SNPs) in lipid metabolism genes in the adolescent population-based Western Australian Pregnancy (Raine) Cohort. METHODS A total 951 seventeen year-olds underwent hepatic ultrasound, anthropometric and biochemical characterization, DNA extraction and genotyping for 57 SNPs in seven lipid metabolism genes (ApoB100, ATGL, ABHD5, MTTP, CETP, SREBP-1c, PPARα). Associations were adjusted for metabolic factors and Bonferroni corrected. RESULTS The prevalence of FLD was 16.2% (11.4% male vs 21.2% female, P=0.001). Multivariate analysis of metabolic factors found suprailiac skinfold thickness (SST) to be the major predictor of FLD in females and males (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08-1.15, P=1.7×10(-10) and OR 1.17, 95%CI 1.13-1.22, P=2.4×10(-11) , respectively). In females, two SNPs in linkage disequilibrium from the CETP gene were associated with FLD: rs12447924 (OR 2.16, 95%CI 1.42-3.32, P=0.0003) and rs12597002 (OR=2.22, 95%CI 1.46-3.41 P=0.0002). In lean homozygotes, the probability of FLD was over 30%, compared with 10-15% in lean heterozygotes and 3-5% in lean wild-types. However, these associations were modified by SST, such that for obese individuals, the probability of FLD was over 30% in all genotype groups. CONCLUSIONS Cholesteryl ester transfer protein gene polymorphisms are associated with an increased risk of FLD in adolescent females. The effect is independent of adiposity in homozygotes, thereby placing lean individuals at a significant risk of FLD.
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Affiliation(s)
- Leon A Adams
- School of Medicine and Pharmacology, The University of Western Australia (UWA), Australia.
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Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 35:32-41. [PMID: 22093607 DOI: 10.1016/j.gastrohep.2011.08.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 12/25/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge.
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Affiliation(s)
- Ruben Hernaez
- Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
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42
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Broos S, Windelinckx A, De Mars G, Huygens W, Peeters MW, Aerssens J, Vlietinck R, Beunen GP, Thomis MA. Is PPARα intron 7 G/C polymorphism associated with muscle strength characteristics in nonathletic young men? Scand J Med Sci Sports 2011; 23:494-500. [PMID: 22092351 DOI: 10.1111/j.1600-0838.2011.01406.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2011] [Indexed: 11/30/2022]
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor, regulates fatty acid metabolism in heart and skeletal muscle. The intron 7 G/C polymorphism (rs4253778) has been associated with athletic performance. The rare C-allele was predominant in power athletes, whereas the G-allele was more frequent in endurance athletes. In the present study, we investigated the association between this polymorphism and strength characteristics in nonathletic, healthy young adults (n = 500; age 24.2 ± 4.4 years). Knee torque was measured during concentric knee flexion and extension movements at 60°/s, 120°/s, and 240°/s during 3, 25, and 5 repetitions, respectively. Also, resistance to muscle fatigue (i.e. work last 20% repetitions/work first 20% repetitions *100) was calculated. Differences in knee strength phenotypes between GG homozygous individuals and C-allele carriers were analyzed. The polymorphism did not influence the ability to produce isometric or dynamic knee flexor or extensor peak torque during static or dynamic conditions in this population (0.23 < P < 0.95). Similar results were found for the endurance ratio, a measure for resistance to muscle fatigue. In conclusion, the PPARα intron 7 G/C polymorphism does not seem to influence strength characteristics in a nonathletic population.
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Affiliation(s)
- S Broos
- Research Center for Exercise and Health, Department of Biomedical Kinesiology, FaBeR, K.U.Leuven, Heverlee, Belgium
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Tailleux A, Wouters K, Staels B. Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:809-18. [PMID: 22056763 DOI: 10.1016/j.bbalip.2011.10.016] [Citation(s) in RCA: 205] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 10/14/2011] [Accepted: 10/18/2011] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a liver pathology with increasing prevalence due to the obesity epidemic. Hence, NAFLD represents a rising threat to public health. Currently, no effective treatments are available to treat NAFLD and its complications such as cirrhosis and liver cancer. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. Here we review recent findings on the pathophysiological role of PPARs in the different stages of NAFLD, from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidence for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis toward irreversible, more advanced lesions. Presently, large controlled trials of long duration are needed to assess the long-term clinical benefits of PPAR agonists in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
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Affiliation(s)
- Anne Tailleux
- Université Lille Nord de France, F-59000 Lille, France
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Di Rosa M, Malaguarnera L. Genetic variants in candidate genes influencing NAFLD progression. J Mol Med (Berl) 2011; 90:105-18. [PMID: 21894552 DOI: 10.1007/s00109-011-0803-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 08/08/2011] [Accepted: 08/08/2011] [Indexed: 12/17/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder including simple steatosis and nonalcoholic steatohepatitis (NASH). Advanced stages of NASH result ultimately in fibrosis, cirrhosis, and hepatocarcinoma. A diagnosis of NASH entails an increased risk of both liver-related and cardiovascular mortality as worsening of the metabolic syndrome. Because of its escalation, many investigations have been performed to elucidate the pathophysiologic origins of the disease progression. Human epidemiologic studies describing polymorphisms in a number of genes involved in metabolic dysfunctions have contributed to clarify the causes leading to the disease evolution. In this review, we attempt to outline critically the most recently identified genetic variants in NAFLD patients to identify possible risk factors promoting the progression of the disease. The evaluation of altered genotypes together with other clinical variables may facilitate the clinical management of these patients.
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Affiliation(s)
- Michelino Di Rosa
- Department of Biomedical Sciences, University of Catania, Via Androne, 83, 95124 Catania, Italy
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Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res 2011; 52:593-617. [PMID: 21245030 DOI: 10.1194/jlr.r008896] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Amanda J Hooper
- Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia
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Rakhshandehroo M, Knoch B, Müller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res 2010; 2010:612089. [PMID: 20936127 PMCID: PMC2948931 DOI: 10.1155/2010/612089] [Citation(s) in RCA: 565] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2010] [Accepted: 08/09/2010] [Indexed: 12/11/2022] Open
Abstract
The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.
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Affiliation(s)
- Maryam Rakhshandehroo
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
| | - Bianca Knoch
- Food, Metabolism & Microbiology, Food & Textiles Group, AgResearch, Palmerston North 4442, New Zealand
- Institute of Food, Nutrition & Human Health, Massey University, Tennent Drive, Palmerston North 4442, New Zealand
| | - Michael Müller
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
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Dongiovanni P, Rametta R, Fracanzani AL, Benedan L, Borroni V, Maggioni P, Maggioni M, Fargion S, Valenti L. Lack of association between peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: a case control study. BMC Gastroenterol 2010; 10:102. [PMID: 20825652 PMCID: PMC2944335 DOI: 10.1186/1471-230x-10-102] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2010] [Accepted: 09/08/2010] [Indexed: 12/12/2022] Open
Abstract
Background Peroxisome proliferator-activated receptors (PPARs) play key roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Aim to assess the effect of functional single nucleotide polymorphisms (SNPs) of PPARα and PPARγ2, previously associated with insulin resistance and dyslipidemia, on liver damage in NAFLD, whose progression is influenced by metabolic abnormalities and inherited factors. Methods The Leu162Val PPARα and Pro12Ala PPARγ2 SNPs were evaluated by restriction analysis. We considered 202 Italian patients with biopsy-proven NAFLD. Results The frequency of the evaluated SNPs did not differ between patients and 346 healthy controls. The presence of the PPARα 162Val allele (prevalence 57%), but not of the PPARγ2 12Ala allele (prevalence 18%), was associated with higher insulin resistance (HOMA-IR index 4.71 ± 3.8 vs. 3.58 ± 2.7, p = 0.026), but not with hyperglycemia. The PPARα 162Val and PPARγ2 12Ala alleles were not associated with the severity of steatosis, necroinflammation, or fibrosis. Conclusions The presence of the PPARα 162Val allele was associated with insulin resistance, but not with liver damage in NAFLD. Because of the limited power of the present sample, larger studies are needed to exclude a minor effect of the PPARγ2 12Ala allele on necroinflammation/fibrosis in NAFLD.
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Affiliation(s)
- Paola Dongiovanni
- Department of Internal Medicine, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione Ospedale Policlinico Ca' Granda IRCCS, Milano, Italy
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Tilg H, Moschen A. Update on nonalcoholic fatty liver disease: genes involved in nonalcoholic fatty liver disease and associated inflammation. Curr Opin Clin Nutr Metab Care 2010; 13:391-6. [PMID: 20473151 DOI: 10.1097/mco.0b013e32833a87cc] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide. Advanced age, extensive overweight and a number of features of the metabolic syndrome are associated with NAFLD severity. The cause of NAFLD is considered multifactorial with a substantial genetic component. RECENT FINDINGS Family members of children with NAFLD demonstrate a higher risk for NAFLD. Whereas such an association only suggests that familial factors are major determinants of whether or not an individual will develop NAFLD, recent genome-wide association studies were able to identify first candidate genes. An allele in patatin-like phospholipase 3, encoding a protein of unknown function with homology to lipid acyl hydrolases, is strongly associated with increased hepatic fat and inflammation. Apolipoprotein C3 gene variants are also associated with NAFLD and insulin resistance. Several other genetic variants have been identified, although with less convincing evidence. These genetic variants involve molecules regulating insulin signaling, lipid metabolism, oxidative stress or fibrogenesis. Furthermore, genetic variants of several cytokines and adipocytokines have been associated with NAFLD. SUMMARY Several genetic factors such as patatin-like phospholipase 3 or apolipoprotein C3 have been recently characterized in NAFLD. Further studies to identify their interaction with environmental factors are eagerly warranted.
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Affiliation(s)
- Herbert Tilg
- Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria.
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Nohara A, Kobayashi J, Mabuchi H. Retinoid X receptor heterodimer variants and cardiovascular risk factors. J Atheroscler Thromb 2009; 16:303-18. [PMID: 19672026 DOI: 10.5551/jat.no786] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis.This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.
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Affiliation(s)
- Atsushi Nohara
- Departments of Lipidology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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