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Wang JJ, Chen XY, Zhang YR, Shen Y, Zhu ML, Zhang J, Zhang JJ. Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease. Front Physiol 2025; 16:1562848. [PMID: 40166716 PMCID: PMC11955510 DOI: 10.3389/fphys.2025.1562848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.
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Affiliation(s)
- Jun-Jie Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Xiao-Yuan Chen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Yi-Rong Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Yan Shen
- Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China
| | - Meng-Lin Zhu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
| | - Jun-Jie Zhang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Department of Basic Medicine, Gannan Medical University, Ganzhou, China
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Li J, Liu X, Tran TT, Lee M, Tsai RYL. DNA Methylation and Target Gene Expression in Fatty Liver Progression From Simple Steatosis to Advanced Fibrosis. Liver Int 2025; 45:e70040. [PMID: 39982030 DOI: 10.1111/liv.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND AND AIM Metabolic dysfunction-associated steatotic liver diseases (MASLD), also known as non-alcoholic fatty liver diseases (NAFLD), have become a leading risk factor for hepatocellular carcinoma (HCC) in Western countries. NAFLD progresses from simple steatosis to HCC, with advanced liver fibrosis (ALF) and metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) representing the two preceding high-risk stages. METHODS We analysed changes in the DNA methylation landscape from simple steatosis to ALF or NASH and determined their relevance in gene regulation and HCC survival. Methylomic datasets generated from applying the Illumina 450K BeadChip on human MASLD/NAFLD liver samples were analysed using integrative data analyses to identify differentially methylated regions (DMRs) associated with ALF (F3/4 vs. F0/1) or non-fibrotic NASH (NASH-F0/1 vs. NAFLD-F0/1). RESULTS Gene Set Enrichment Analysis (GSEA) of genes associated with fibrosis-DMRs showed enrichment in xenobiotic metabolism, UV response and hypoxia pathways. Expression of 25 DMR-associated genes showed significant associations with HCC survival outcomes, including 16 genes with fibrosis-DMRs and 2 with NASH-DMRs mapped to their promoter regions. Binding motifs of seven transcription factors (TFs) were enriched in fibrosis-DMRs. Four DMR-associated genes (ESR1, TYW3, CLGN and TUBB) displayed an inverse relationship between promoter methylation and gene expression during human MASLD progression, which was further validated in a mouse MASLD model. CONCLUSIONS We propose a model in which changes in promoter DNA methylation during NAFLD progression regulate gene expression, impacting HCC survival outcomes.
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Affiliation(s)
- Jin Li
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Xiaoqin Liu
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
- Department of Translational Medical Sciences, School of Medicine, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Tran T Tran
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
| | - Miryoung Lee
- Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, Texas, USA
| | - Robert Y L Tsai
- Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA
- Department of Translational Medical Sciences, School of Medicine, Texas A&M University Health Science Center, Houston, Texas, USA
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Stols-Gonçalves D, Meijnikman AS, Tristão LS, dos Santos CL, Denswil NP, Verheij J, Bernardo WM, Nieuwdorp M. Metabolic Dysfunction-Associated Steatotic Liver Disease and Alcohol-Associated Liver Disease: Liver DNA Methylation Analysis-A Systematic Review. Cells 2024; 13:1893. [PMID: 39594641 PMCID: PMC11592595 DOI: 10.3390/cells13221893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/29/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading causes of liver disease worldwide. The exact roles of epigenetic factors in both diseases remains largely unknown. In this context, liver DNA methylation remains a field that requires further exploration and understanding. METHODS We performed a systematic review of liver DNA methylation in humans with MASLD or ALD using Ovid MEDLINE, Ovid Embase, and Cochrane Library. We included human studies where liver DNA methylation was assessed in patients with MASLD and/or ALD. The Rayyan platform was used to select studies. Risk of bias was assessed with the "risk of bias in non-randomized studies of interventions" tool, ROBINS-I. We performed pathway analysis using the most important differentially methylated genes selected in each article. RESULTS Fifteen articles were included in this systematic review. The risk of bias was moderate to serious in all articles and bias due to confounding and patient selection was high. Sixteen common pathways, containing differentially methylated genes, including cancer pathways, were identified in both diseases. CONCLUSIONS There are common pathways, containing differentially methylated genes, in ALD and MASLD, such as pathways in cancer and peroxisome proliferator-activated receptor (PPAR) signaling pathways. In MASLD, the insulin signaling pathway is one of the most important, and in ALD, the MAPK signaling pathway is the most important. Our study adds one more piece to the puzzle of the mechanisms involved in steatotic liver disease.
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Affiliation(s)
- Daniela Stols-Gonçalves
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Meibergdreef 9 (Room A01-112), 1105 AZ Amsterdam, The Netherlands; (A.S.M.); (M.N.)
| | - Abraham S. Meijnikman
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Meibergdreef 9 (Room A01-112), 1105 AZ Amsterdam, The Netherlands; (A.S.M.); (M.N.)
| | - Luca Schiliró Tristão
- Department of Evidence-Based Medicine, Faculdade de Ciências Médicas de Santos—Lusiada University Center, Santos 11050-071, SP, Brazil; (L.S.T.); (C.L.d.S.); (W.M.B.)
| | - Clara Lucato dos Santos
- Department of Evidence-Based Medicine, Faculdade de Ciências Médicas de Santos—Lusiada University Center, Santos 11050-071, SP, Brazil; (L.S.T.); (C.L.d.S.); (W.M.B.)
| | - Nerissa P. Denswil
- Medical Library, Amsterdam University Medical Centre, University of Amsterdam, 1012 WP Amsterdam, The Netherlands;
| | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centre, 1105 AZ Amsterdam, The Netherlands;
| | - Wanderley M. Bernardo
- Department of Evidence-Based Medicine, Faculdade de Ciências Médicas de Santos—Lusiada University Center, Santos 11050-071, SP, Brazil; (L.S.T.); (C.L.d.S.); (W.M.B.)
- Faculdade de Medicina d Universidade de São Paulo, São Paulo 05508-220, SP, Brazil
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centre, Meibergdreef 9 (Room A01-112), 1105 AZ Amsterdam, The Netherlands; (A.S.M.); (M.N.)
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Moretti V, Romeo S, Valenti L. The contribution of genetics and epigenetics to MAFLD susceptibility. Hepatol Int 2024; 18:848-860. [PMID: 38662298 PMCID: PMC11450136 DOI: 10.1007/s12072-024-10667-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/25/2024] [Indexed: 04/26/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.
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Affiliation(s)
- Vittoria Moretti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Lahnsteiner A, Ellmer V, Oberlercher A, Liutkeviciute Z, Schönauer E, Paulweber B, Aigner E, Risch A. G-quadruplex forming regions in GCK and TM6SF2 are targets for differential DNA methylation in metabolic disease and hepatocellular carcinoma patients. Sci Rep 2024; 14:20215. [PMID: 39215018 PMCID: PMC11364803 DOI: 10.1038/s41598-024-70749-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
The alarming increase in global rates of metabolic diseases (MetDs) and their association with cancer risk renders them a considerable burden on our society. The interplay of environmental and genetic factors in causing MetDs may be reflected in DNA methylation patterns, particularly at non-canonical (non-B) DNA structures, such as G-quadruplexes (G4s) or R-loops. To gain insight into the mechanisms of MetD progression, we focused on DNA methylation and functional analyses on intragenic regions of two MetD risk genes, the glucokinase (GCK) exon 7 and the transmembrane 6 superfamily 2 (TM6SF2) intron 2-exon 3 boundary, which harbor non-B DNA motifs for G4s and R-loops.Pyrosequencing of 148 blood samples from a nested cohort study revealed significant differential methylation in GCK and TM6SF2 in MetD patients versus healthy controls. Furthermore, these regions harbor hypervariable and differentially methylated CpGs also in hepatocellular carcinoma versus normal tissue samples from The Cancer Genome Atlas (TCGA). Permanganate/S1 nuclease footprinting with direct adapter ligation (PDAL-Seq), native polyacrylamide DNA gel electrophoresis and circular dichroism (CD) spectroscopy revealed the formation of G4 structures in these regions and demonstrated that their topology and stability is affected by DNA methylation. Detailed analyses including histone marks, chromatin conformation capture data, and luciferase reporter assays, highlighted the cell-type specific regulatory function of the target regions. Based on our analyses, we hypothesize that changes in DNA methylation lead to topological changes, especially in GCK exon 7, and cause the activation of alternative regulatory elements or potentially play a role in alternative splicing.Our analyses provide a new view on the mechanisms underlying the progression of MetDs and their link to hepatocellular carcinomas, unveiling non-B DNA structures as important key players already in early disease stages.
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Affiliation(s)
- Angelika Lahnsteiner
- Division of Cancer (Epi-)Genetics, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020, Salzburg, Austria.
- Cancer Cluster Salzburg, Salzburg, Austria.
| | - Victoria Ellmer
- Division of Cancer (Epi-)Genetics, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020, Salzburg, Austria
| | - Anna Oberlercher
- Division of Cancer (Epi-)Genetics, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020, Salzburg, Austria
| | - Zita Liutkeviciute
- Division of Cancer (Epi-)Genetics, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020, Salzburg, Austria
| | - Esther Schönauer
- Division of Structural Biology, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Salzburg, Austria
| | - Bernhard Paulweber
- First Department of Medicine, University Clinic Salzburg, Salzburg, Austria
| | - Elmar Aigner
- First Department of Medicine, University Clinic Salzburg, Salzburg, Austria
- Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Angela Risch
- Division of Cancer (Epi-)Genetics, Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology (CTBI), Paris Lodron University Salzburg, Hellbrunnerstraße 34, 5020, Salzburg, Austria
- Cancer Cluster Salzburg, Salzburg, Austria
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Vidal-Cevallos P, Sorroza-Martínez AP, Chávez-Tapia NC, Uribe M, Montalvo-Javé EE, Nuño-Lámbarri N. The Relationship between Pathogenesis and Possible Treatments for the MASLD-Cirrhosis Spectrum. Int J Mol Sci 2024; 25:4397. [PMID: 38673981 PMCID: PMC11050641 DOI: 10.3390/ijms25084397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.
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Affiliation(s)
- Paulina Vidal-Cevallos
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
| | | | - Norberto C. Chávez-Tapia
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
| | - Eduardo E. Montalvo-Javé
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico; (P.V.-C.); (N.C.C.-T.); (M.U.); (E.E.M.-J.)
- Department of Surgery, Faculty of Medicine, Universidad Nacional Autónoma de Mexico, Mexico City 04360, Mexico
- Hepatopancreatobiliary Clinic, Department of Surgery, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
| | - Natalia Nuño-Lámbarri
- Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
- Department of Surgery, Faculty of Medicine, Universidad Nacional Autónoma de Mexico, Mexico City 04360, Mexico
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7
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Ramezani M, Zobeiry M, Abdolahi S, Hatami B, Zali MR, Baghaei K. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251:154809. [PMID: 37797383 DOI: 10.1016/j.prp.2023.154809] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches.
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Affiliation(s)
- Meysam Ramezani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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8
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Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis. Exp Mol Med 2023; 55:143-157. [PMID: 36609599 PMCID: PMC9898513 DOI: 10.1038/s12276-022-00919-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/17/2022] [Accepted: 11/13/2022] [Indexed: 01/07/2023] Open
Abstract
Dynamic alteration of DNA methylation leads to various human diseases, including nonalcoholic fatty liver disease (NAFLD). Although C-Maf-inducing protein (Cmip) has been reported to be associated with NAFLD, its exact underlying mechanism remains unclear. Here, we aimed to elucidate this mechanism in NAFLD in vitro and in vivo. We first identified alterations in the methylation status of the Cmip intron 1 region in mouse liver tissues with high-fat high-sucrose diet-induced NAFLD. Knockdown of DNA methyltransferase (Dnmt) 1 significantly increased Cmip expression. Chromatin immunoprecipitation assays of AML12 cells treated with oleic and palmitic acid (OPA) revealed that Dnmt1 was dissociated and that methylation of H3K27me3 was significantly decreased in the Cmip intron 1 region. Conversely, the knockdown of Tet methylcytosine dioxygenase 2 (Tet2) decreased Cmip expression. Following OPA treatment, the CCCTC-binding factor (Ctcf) was recruited, and H3K4me3 was significantly hypermethylated. Intravenous Cmip siRNA injection ameliorated NAFLD pathogenic features in ob/ob mice. Additionally, Pparγ and Cd36 expression levels were dramatically decreased in the livers of ob/ob mice administered siCmip, and RNA sequencing revealed that Gbp2 was involved. Gbp2 knockdown also induced a decrease in Pparγ and Cd36 expression, resulting in the abrogation of fatty acid uptake into cells. Our data demonstrate that Cmip and Gbp2 expression levels are enhanced in human liver tissues bearing NAFLD features. We also show that Dnmt1-Trt2/Ctcf-mediated reversible modulation of Cmip methylation regulates the Gbp2-Pparγ-Cd36 signaling pathway, indicating the potential of Cmip as a novel therapeutic target for NAFLD.
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9
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Wattacheril JJ, Raj S, Knowles DA, Greally JM. Using epigenomics to understand cellular responses to environmental influences in diseases. PLoS Genet 2023; 19:e1010567. [PMID: 36656803 PMCID: PMC9851565 DOI: 10.1371/journal.pgen.1010567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD.
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Affiliation(s)
- Julia J. Wattacheril
- Department of Medicine, Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, New York, United States of America
| | - Srilakshmi Raj
- Division of Genomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - David A. Knowles
- New York Genome Center, New York, New York, United States of America
- Department of Computer Science, Columbia University, New York, New York, United States of America
- Department of Systems Biology, Columbia University, New York, New York, United States of America
| | - John M. Greally
- Division of Genomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America
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Moylan CA, Mavis AM, Jima D, Maguire R, Bashir M, Hyun J, Cabezas MN, Parish A, Niedzwiecki D, Diehl AM, Murphy SK, Abdelmalek MF, Hoyo C. Alterations in DNA methylation associate with fatty liver and metabolic abnormalities in a multi-ethnic cohort of pre-teenage children. Epigenetics 2022; 17:1446-1461. [PMID: 35188871 PMCID: PMC9586600 DOI: 10.1080/15592294.2022.2039850] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/09/2022] [Accepted: 02/01/2022] [Indexed: 11/03/2022] Open
Abstract
Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90 mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7-12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3-13.4%) and MRE was 2.5 kPa (range, 1.5-3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR<5%). The top two CpGs, cg25474373 and cg07264203, mapped to or near RFTN2 and PRICKLE2 genes. These two CpG sites were also significantly associated with a NAFLD diagnosis. As higher LFC associates with an adverse cardiometabolic profile already in childhood, altered DNAm may identify these children early in disease course for targeted intervention. Larger, longitudinal studies are needed to validate these findings and determine mechanistic relevance.
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Affiliation(s)
- Cynthia A. Moylan
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alisha M. Mavis
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
| | - Dereje Jima
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Rachel Maguire
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Mustafa Bashir
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Jeongeun Hyun
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Melanie N. Cabezas
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alice Parish
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Donna Niedzwiecki
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Anna Mae Diehl
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Susan K. Murphy
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Manal F. Abdelmalek
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Cathrine Hoyo
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
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11
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Dai L, Xu J, Liu B, Dang Y, Wang R, Zhuang L, Li D, Jiao L, Wang J, Zhang L, Zhong LLD, Zhou W, Ji G. Lingguizhugan Decoction, a Chinese herbal formula, improves insulin resistance in overweight/obese subjects with non-alcoholic fatty liver disease: a translational approach. Front Med 2022; 16:745-759. [PMID: 35471471 DOI: 10.1007/s11684-021-0880-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/25/2021] [Indexed: 12/12/2022]
Abstract
Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ⩾ 24 kg/m2; lean, BMI < 24 kg/m2). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (-0.19 (1.47) versus 0.08 (1.99), P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.
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Affiliation(s)
- Liang Dai
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- Clinical Research Academy, Peking University Shenzhen Hospital, Shenzhen, 518032, China
| | - Jingjuan Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- Department of Integrated Traditional and Western Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China
| | - Baocheng Liu
- Shanghai Innovation Centre of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Ruirui Wang
- Shanghai Innovation Centre of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lijie Zhuang
- Sanlin Health Centre of Pudong New District, Shanghai, 200120, China
| | - Dong Li
- Zhangjiang Health Centre of Pudong New District, Shanghai, 201203, China
| | - Lulu Jiao
- Beicai Health Centre of Pudong New District, Shanghai, 201204, China
| | - Jianying Wang
- Shanghai Innovation Centre of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lei Zhang
- Shanghai Innovation Centre of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Linda L D Zhong
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- Hong Kong Chinese Medicine Study Centre, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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12
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Saffo S, Do A. Clinical Phenotyping and the Application of Precision Medicine in MAFLD. Clin Liver Dis (Hoboken) 2022; 19:227-233. [PMID: 35795621 PMCID: PMC9248929 DOI: 10.1002/cld.1199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/02/2021] [Accepted: 12/15/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Audio Recording.
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Affiliation(s)
- Saad Saffo
- Section of Digestive DiseasesYale University School of MedicineNew HavenCT
| | - Albert Do
- Section of Digestive DiseasesYale University School of MedicineNew HavenCT
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13
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Bae J, Kim JE, Perumalsamy H, Park S, Kim Y, Jun DW, Yoon TH. Mass Cytometry Study on Hepatic Fibrosis and Its Drug-Induced Recovery Using Mouse Peripheral Blood Mononuclear Cells. Front Immunol 2022; 13:814030. [PMID: 35222390 PMCID: PMC8863676 DOI: 10.3389/fimmu.2022.814030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/03/2022] [Indexed: 01/10/2023] Open
Abstract
The number of patients with liver diseases has increased significantly with the progress of global industrialization. Hepatic fibrosis, one of the most common liver diseases diagnosed in many developed countries, occurs in response to chronic liver injury and is primarily driven by the development of inflammation. Earlier immunological studies have been focused on the importance of the innate immune response in the pathophysiology of steatohepatitis and fibrosis, but recently, it has also been reported that adaptive immunity, particularly B cells, plays an essential role in hepatic inflammation and fibrosis. However, despite recent data showing the importance of adaptive immunity, relatively little is known about the role of B cells in the pathogenesis of steatohepatitis fibrosis. In this study, a single-cell-based, high-dimensional mass cytometric investigation of the peripheral blood mononuclear cells collected from mice belonging to three groups [normal chow (NC), thioacetamide (TAA), and 11beta-HSD inhibitor drug] was conducted to further understand the pathogenesis of liver fibrosis through reliable noninvasive biomarkers. Firstly, major immune cell types and their population changes were qualitatively analyzed using UMAP dimensionality reduction and two-dimensional visualization technique combined with a conventional manual gating strategy. The population of B cells displayed a twofold increase in the TAA group compared to that in the NC group, which was recovered slightly after treatment with the 11beta-HSD inhibitor drug. In contrast, the populations of NK cells, effector CD4+ T cells, and memory CD8+ T cells were significantly reduced in the TAA group compared with those in the NC group. Further identification and quantification of the major immune cell types and their subsets were conducted based on automated clustering approaches [PhenoGraph (PG) and FlowSOM]. The B-cell subset corresponding to PhenoGraph cluster PG#2 (CD62LhighCD44highLy6chigh B cells) and PG#3 (CD62LhighCD44highLy6clow B cell) appears to play a major role in both the development of hepatic fibrosis and recovery via treatment, whereas PG#1 (CD62LlowCD44highLy6clow B cell) seems to play a dominant role in the development of hepatic fibrosis. These findings provide insights into the roles of cellular subsets of B cells during the progression of, and recovery from, hepatic fibrosis.
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Affiliation(s)
- Jiwon Bae
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea
| | - Ji Eun Kim
- Department of Internal Medicine, Hanyang University Hospital, Seoul, South Korea
| | - Haribalan Perumalsamy
- Research Institute for Convergence of Basic Science, Hanyang University, Seoul, South Korea
| | - Sehee Park
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea
| | - Yun Kim
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul, South Korea.,Department of Clinical Pharmacology and Therapeutics, Hanyang University Hospital, Seoul, South Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Seoul, South Korea.,Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul, South Korea.,Department of Medical and Digital Engineering, College of Engineering, Hanyang University, Seoul, South Korea
| | - Tae Hyun Yoon
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea.,Research Institute for Convergence of Basic Science, Hanyang University, Seoul, South Korea.,Institute of Next Generation Material Design, Hanyang University, Seoul, South Korea.,Yoon Idea Lab. Co. Ltd, Seoul, South Korea
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14
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Kemas AM, Youhanna S, Lauschke VM. Non-alcoholic fatty liver disease - opportunities for personalized treatment and drug development. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2022. [DOI: 10.1080/23808993.2022.2053285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Aurino M. Kemas
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Sonia Youhanna
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M. Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tuebingen, Tuebingen, Germany
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15
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New advances of DNA/RNA methylation modification in liver fibrosis. Cell Signal 2021; 92:110224. [PMID: 34954394 DOI: 10.1016/j.cellsig.2021.110224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022]
Abstract
Liver fibrosis is a complex pathological process caused by multiple pathogenic factors，such as ethanol, viruses, toxins, drugs or cholestasis, and it can eventually develop into liver cirrhosis without effective treatment. Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in the pathogenesis of liver fibrosis. However, the pathogenesis of liver fibrosis has not been fully elucidated. DNA/RNA methylation can regulate gene expression without alteration in its sequence, and numerous studies have shown the involvement of DNA methylation in the activation of HSCs and then promote the progression of liver fibrosis. In addition, RNA methylation has recently been reported to play a regulatory role in this process. In this review, we focus on the aberrant DNA/RNA methylation of selected genes and explore their functional mechanism in regulating HSCs activation and liver fibrogenesis. All of these findings will enhance our understanding of DNA/RNA methylation and their roles in liver fibrosis and provide the basis to identify effective therapeutic targets.
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16
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Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
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17
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Johnson ND, Wu X, Still CD, Chu X, Petrick AT, Gerhard GS, Conneely KN, DiStefano JK. Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clin Epigenetics 2021; 13:152. [PMID: 34353365 PMCID: PMC8340447 DOI: 10.1186/s13148-021-01129-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. RESULTS Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p < 5.96 × 10-8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. CONCLUSION These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.
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Affiliation(s)
- Nicholas D Johnson
- Department of Human Genetics, Emory University, Atlanta, GA, USA.,Population Biology, Ecology, and Evolution Program, Emory University, Atlanta, GA, USA
| | - Xiumei Wu
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Xin Chu
- Geisinger Obesity Institute, Danville, PA, USA
| | | | - Glenn S Gerhard
- Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Karen N Conneely
- Department of Human Genetics, Emory University, Atlanta, GA, USA.,Population Biology, Ecology, and Evolution Program, Emory University, Atlanta, GA, USA
| | - Johanna K DiStefano
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, Phoenix, AZ, USA.
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18
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Arechederra M, Recalde M, Gárate-Rascón M, Fernández-Barrena MG, Ávila MA, Berasain C. Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease. Cancers (Basel) 2021; 13:1265. [PMID: 33809263 PMCID: PMC7998165 DOI: 10.3390/cancers13061265] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.
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Affiliation(s)
- María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
| | - María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (M.R.); (M.G.-R.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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19
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Ramos LF, Silva CM, Pansa CC, Moraes KCM. Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver. Expert Rev Gastroenterol Hepatol 2021; 15:25-40. [PMID: 32892668 DOI: 10.1080/17474124.2020.1820321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed. AREAS COVERED This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized. EXPERT OPINION Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
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Affiliation(s)
- Letícia F Ramos
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Caio M Silva
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Camila C Pansa
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
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20
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Asif S, Morrow NM, Mulvihill EE, Kim KH. Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases. Front Genet 2020; 11:590369. [PMID: 33193730 PMCID: PMC7593700 DOI: 10.3389/fgene.2020.590369] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment.
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Affiliation(s)
- Shaza Asif
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Nadya M. Morrow
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Erin E. Mulvihill
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Kyoung-Han Kim
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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21
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Li K, Qin L, Jiang S, Li A, Zhang C, Liu G, Sun J, Sun H, Zhao Y, Li N, Zhang Y. The signature of HBV-related liver disease in peripheral blood mononuclear cell DNA methylation. Clin Epigenetics 2020; 12:81. [PMID: 32513305 PMCID: PMC7278209 DOI: 10.1186/s13148-020-00847-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/08/2020] [Indexed: 12/20/2022] Open
Abstract
Background Hepatitis B virus (HBV)-related liver disease induces liver damage by hepatic immune and inflammatory response. The association between aberrant peripheral blood mononuclear cell (PBMC) DNA methylation and progression of liver disease and fibrosis remains unclear. Results Here we applied Infinium 450 K BeadChip investigating PBMC genome-wide methylation profiling of 48 HBV-related liver disease patients including 24 chronic hepatitis B (CHB), 14 compensated liver cirrhosis (LC), and 10 decompensated liver cirrhosis (DLC). In total, there were 7888 differentially methylated CpG sites (36.06% hypermethylation, 63.94% hypomethylation) correlate with liver disease progression. LC was difficult to be diagnosed, intermediating between CHB and DLC. We used least absolute shrinkage and selection operator (LASSO)-logistic regression method to perform a LC predictive model. The predicted probability (P) of having LC was estimated by the combined model: P = 1/(1 − e−x), where X = 11.52 − 2.82 × (if AST within the normal range − 0.19 × (percent methylation of cg05650055) − 0.21 × (percent methylation of cg17149911 ). Pyrosequencing validation and confusion matrix analysis was used for internal testing, area under receiver operating characteristic curve (AUROC) of model was 0.917 (95% CI, 0.80–0.977). On the fibrosis progress, there were 1705 genes in LC compared with CHB, whose differentially methylated CpG sites loading within the “promoter” regions (including TSS1500, TSS200, 5′UTR, and the 1st exon of genes) subject into the enrichment analysis using Ingenuity Pathway Analysis (IPA). There were 113 enriched immune-related pathways indicated that HBV-related liver fibrosis progression caused epigenetic reprogramming of the immune and inflammatory response. Conclusions These data support idea that development of HBV-related chronic liver disease is linked with robust and broad alteration of methylation in peripheral immune system. CpG methylation sites serve as relevant biomarker candidates to monitor and diagnose LC, providing new insight into the immune mechanisms understanding the progression of HBV-related liver fibrosis and cirrhosis.
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Affiliation(s)
- Kang Li
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China
| | - Ling Qin
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China.,Schools of Basic Medical Science, Capital Medical University, Beijing, China
| | | | - Ang Li
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China
| | - Chi Zhang
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China
| | - Guihai Liu
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China.,University of Oxford, Oxford, UK
| | - Jianping Sun
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China
| | - Huanqing Sun
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China
| | - Yan Zhao
- Clinical Laboratory Center, Beijing You'An hospital, Capital Medical University, Beijing, China
| | - Ning Li
- Departments of Hepatobiliary Surgery, Beijing You'An Hospital, Capital Medical University, Beijing, China.
| | - Yonghong Zhang
- Biomedical Information Center, Beijing You'An Hospital, Capital Medical University, Beijing, China.
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Xin FZ, Zhao ZH, Zhang RN, Pan Q, Gong ZZ, Sun C, Fan JG. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα. World J Gastroenterol 2020; 26:2203-2220. [PMID: 32476787 PMCID: PMC7235203 DOI: 10.3748/wjg.v26.i18.2203] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/27/2020] [Accepted: 04/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown. AIM To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH. METHODS Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism. RESULTS Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, β-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis. CONCLUSION Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.
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Affiliation(s)
- Feng-Zhi Xin
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ze-Hua Zhao
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zi-Zhen Gong
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chao Sun
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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Geurtsen ML, Jaddoe VWV, Salas LA, Santos S, Felix JF. Newborn and childhood differential DNA methylation and liver fat in school-age children. Clin Epigenetics 2019; 12:3. [PMID: 31892367 PMCID: PMC6938624 DOI: 10.1186/s13148-019-0799-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/19/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. RESULTS The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. CONCLUSIONS DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat.
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Affiliation(s)
- Madelon L Geurtsen
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, the Netherlands.,Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Vincent W V Jaddoe
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, the Netherlands.,Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Lucas A Salas
- Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Susana Santos
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, the Netherlands.,Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Janine F Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, the Netherlands. .,Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
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Sinton MC, Hay DC, Drake AJ. Metabolic control of gene transcription in non-alcoholic fatty liver disease: the role of the epigenome. Clin Epigenetics 2019; 11:104. [PMID: 31319896 PMCID: PMC6637519 DOI: 10.1186/s13148-019-0702-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 07/09/2019] [Indexed: 01/30/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.
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Affiliation(s)
- Matthew C Sinton
- University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - David C Hay
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Amanda J Drake
- University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
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D'Adamo E, Castorani V, Nobili V. The Liver in Children With Metabolic Syndrome. Front Endocrinol (Lausanne) 2019; 10:514. [PMID: 31428049 PMCID: PMC6687849 DOI: 10.3389/fendo.2019.00514] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as an emerging health risk in obese children and adolescents. NAFLD represents a wide spectrum of liver conditions, ranging from asymptomatic steatosis to steatohepatitis. The growing prevalence of fatty liver disease in children is associated with an increased risk of metabolic and cardiovascular complications. NAFLD is considered the hepatic manifestation of Metabolic Syndrome (MetS) and several lines of evidence have reported that children with NAFLD present one or more features of MetS. The pathogenetic mechanisms explaining the interrelationships between fatty liver disease and MetS are not clearly understood. Altough central obesity and insulin resistance seem to represent the core of the pathophysiology in both diseases, genetic susceptibility and enviromental triggers are emerging as crucial components promoting the development of NAFLD and MetS in children. In the present review we have identified and summarizied studies discussing current pathogenetic data of the association between NAFLD and MetS in children.
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Affiliation(s)
- Ebe D'Adamo
- Department of Neonatology, University of Chieti, Chieti, Italy
- *Correspondence: Ebe D'Adamo
| | | | - Valerio Nobili
- Department of Pediatrics, University “La Sapienza”, Rome, Italy
- Hepatology, Gastroenterology and Nutrition Unit, IRCCS “Bambino Gesù” Children's Hospital, Rome, Italy
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