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4. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

[Argemi J] Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, Pittsburgh, USA. University of Pittsburgh Medical Center (UPMC), Pittsburgh, USA. Liver Unit, Clínica Universidad de Navarra, Navarra, Pamplona. University of Navarra, Pamplona, Spain. [Latasa MU] Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. [Atkinson SR] Division of Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK. [Blokhin IO] Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, USA. [Massey V] Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, USA. [Gue JP] Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, Pittsburgh, USA. University of Pittsburgh Medical Center (UPMC), Pittsburgh, USA. [Altamirano J] Servei de Medicina Interna, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Medicina Interna, Hospital Quiron Salud, Barcelona, Spain. and Hospital Universitari Vall d'Hebron

Subjects
Àcids nucleics - Anàlisi, Enfermedades del Sistema Digestivo::Hepatopatías::Hepatitis::Hepatitis Alcohólica [ENFERMEDADES], fenómenos genéticos::regulación de la expresión génica::epigénesis genética [FENÓMENOS Y PROCESOS], Genetic Phenomena::Gene Expression Regulation::Epigenesis, Genetic [PHENOMENA AND PROCESSES], Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, RNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ARN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Epigenètica, Digestive System Diseases::Liver Diseases::Hepatitis::Hepatitis, Alcoholic [DISEASES], Hepatitis
Published
2021

5. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Author

Gemma Odena, Jelena Mann, Lia R. Edmunds, Juan Pablo Arab, Aaron Bell, Stephen R. Atkinson, Pau Sancho-Bru, Satdarshan P.S. Monga, Peter Stärkel, Joel P. Gue, Maria U. Latasa, Juan Caballería, Matías A. Avila, Alexandre Louvet, Sheng Cao, Juan Luis Gomez, Claes Wahlestedt, Marsha Y. Morgan, Juan José Lozano, Philippe Mathurin, José Altamirano, Derek J. Van Booven, Laurent Dubuquoy, Ramon Bataller, Ilya O. Blokhin, Shinji Furuya, Constantino Fondevilla, D. Lansing Taylor, Veronica Massey, Ivan Rusyn, Mark Thursz, Michael J. Jurczak, Tomás J. Aragón, Carolin Lackner, Lawrence Vernetti, Vijay H. Shah, Josepmaria Argemi, Meritxell Ventura-Cots, Joaquín Cabezas, Carmen Berasain, Medical Research Council (MRC), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Universidad de Navarra [Pamplona] (UNAV), Imperial College London, University of Miami Leonard M. Miller School of Medicine (UMMSM), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, University of Pittsburgh School of Medicine, Mayo Clinic [Rochester], University of Barcelona, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University College of London [London] (UCL), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Texas A&M University [College Station], Medical University Graz, Newcastle University [Newcastle], [Argemi J] Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, Pittsburgh, USA. University of Pittsburgh Medical Center (UPMC), Pittsburgh, USA. Liver Unit, Clínica Universidad de Navarra, Navarra, Pamplona. University of Navarra, Pamplona, Spain. [Latasa MU] Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. [Atkinson SR] Division of Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, UK. [Blokhin IO] Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, USA. [Massey V] Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, USA. [Gue JP] Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, Pittsburgh, USA. University of Pittsburgh Medical Center (UPMC), Pittsburgh, USA. [Altamirano J] Servei de Medicina Interna, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Medicina Interna, Hospital Quiron Salud, Barcelona, Spain., Vall d'Hebron Barcelona Hospital Campus, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie, Université de Lille, Inserm, CHU Lille, University of Pittsburgh [PITT], Universidad de Navarra [Pamplona] [UNAV], University of Miami Leonard M. Miller School of Medicine [UMMSM], University of North Carolina [Chapel Hill] [UNC], Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas [CIBERehd], Université Catholique de Louvain = Catholic University of Louvain [UCL], Lille Inflammation Research International Center - U 995 [LIRIC], University College of London [London] [UCL], and Université de Lille, LillOA

Subjects
0301 basic medicine, Male, fenómenos genéticos::regulación de la expresión génica::epigénesis genética [FENÓMENOS Y PROCESOS], SCORING SYSTEM, [SDV]Life Sciences [q-bio], Biopsy, TO-MESENCHYMAL TRANSITION, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, RNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], General Physics and Astronomy, 02 engineering and technology, técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ARN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Adult, Aged, Animals, Chromatin Assembly and Disassembly, DNA Methylation, Disease Progression, Epigenesis, Genetic, Female, Gene Expression Profiling, Gene Expression Regulation, Hepatitis, Alcoholic, Hepatocyte Nuclear Factor 4, Hepatocytes, Humans, Liver, Middle Aged, Polymorphism, Genetic, Sequence Analysis, RNA, Transforming Growth Factor beta1, Gene regulatory networks, Hepatitis, Transcriptome, Gene expression, lcsh:Science, DNA METHYLATION, FACTOR 4-ALPHA ISOFORMS, Regulation of gene expression, Multidisciplinary, 021001 nanoscience & nanotechnology, Alcoholic, 3. Good health, [SDV] Life Sciences [q-bio], Multidisciplinary Sciences, DNA methylation, Science & Technology - Other Topics, GROWTH, 0210 nano-technology, Digestive System Diseases::Liver Diseases::Hepatitis::Hepatitis, Alcoholic [DISEASES], Sequence Analysis, Ciencias de la Salud::Hepatología [Materias Investigacion], SRC, endocrine system, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Chromatin remodeling, Article, 03 medical and health sciences, Genetic, LIVER-DISEASE, Epigenetics, Polymorphism, GENOME-WIDE ASSOCIATION, Gene, Science & Technology, General Chemistry, Alcoholic liver disease, GLUCONEOGENESIS, Epigenètica, Gene expression profiling, Àcids nucleics - Anàlisi, 030104 developmental biology, Genetic Phenomena::Gene Expression Regulation::Epigenesis, Genetic [PHENOMENA AND PROCESSES], Cancer research, RNA, lcsh:Q, PENTOXIFYLLINE, enfermedades del sistema digestivo::enfermedades hepáticas::hepatitis::hepatitis alcohólica [ENFERMEDADES], Epigenesis
Abstract

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH., Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Published
2019

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