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

Adult Aged Animals Biopsy Chromatin Assembly and Disassembly DNA Methylation Disease Progression Epigenesis, Genetic Female Gene Expression Profiling Gene Expression Regulation Hepatitis, Alcoholic / genetics Hepatocyte Nuclear Factor 4 / genetics Hepatocytes / pathology Humans Liver / cytology Male Middle Aged Polymorphism, Genetic Sequence Analysis, RNA Transforming Growth Factor beta1 / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
16 07 2019
Historique:
received: 09 07 2018
accepted: 10 06 2019
entrez: 18 7 2019
pubmed: 18 7 2019
medline: 18 12 2019
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-019-11004-3 PMID: 31311938 PMC: PMC6635373
pubmed: 31311938
doi: 10.1038/s41467-019-11004-3
pii: 10.1038/s41467-019-11004-3
pmc: PMC6635373
doi:

Substances chimiques

Hepatocyte Nuclear Factor 4 0
NR2A3 protein, human 0
TGFB1 protein, human 0
Transforming Growth Factor beta1 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3126

Subventions

Organisme : Medical Research Council
ID : MR/R014019/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK101426
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA021171
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA018663
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062277
Pays : United States
Organisme : NIAAA NIH HHS
ID : R37 AA021171
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007052
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116993
Pays : United States
Organisme : Medical Research Council
ID : MR/K001949/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK114012
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA023781
Pays : United States
Organisme : Medical Research Council
ID : MR/R023026/1
Pays : United Kingdom
Organisme : NIAAA NIH HHS
ID : U01 AA021908
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : Medical Research Council
ID : MR/M003132/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK109365
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR000503
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026972
Pays : United States

Commentaires et corrections

Type : ErratumIn

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Auteurs

Josepmaria Argemi (J)

Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15261, USA.
Liver Unit, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
ORCID: 0000-0003-1696-7753

Maria U Latasa (MU)

Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, 31008, Spain.
ORCID: 0000-0002-0878-1337

Stephen R Atkinson (SR)

Division of Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.

Ilya O Blokhin (IO)

Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.

Veronica 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, NC, 27516, USA.

Joel P Gue (JP)

Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15261, USA.

Joaquin Cabezas (J)

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, NC, 27516, USA.
Departament of Hepatology, Marqués de Valdecilla University Hospital, Santander, 39008, Spain.
ORCID: 0000-0003-0012-484X

Juan J Lozano (JJ)

Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.

Derek Van Booven (D)

John P. Hussman Institute of Human Genomics. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.

Aaron Bell (A)

Departments of Pathology and Medicine, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
ORCID: 0000-0001-6648-0834

Sheng Cao (S)

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA.

Lawrence A Vernetti (LA)

University of Pittsburgh Drug Discovery Institute, Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Juan P Arab (JP)

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA.
Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile.
ORCID: 0000-0002-8561-396X

Meritxell Ventura-Cots (M)

Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15261, USA.
ORCID: 0000-0001-9513-2855

Lia R Edmunds (LR)

Department of Medicine, Division of Endocrinology and Metabolism, Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Constantino Fondevila (C)

Liver Transplant Unit, Department of Surgery, Hospital Clinic, University of Barcelona, Barcelona, 08036, Spain.

Peter Stärkel (P)

Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc and Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, 1200, Belgium.
ORCID: 0000-0003-2938-4442

Laurent Dubuquoy (L)

Service des Maladies de l'appareil digestif, CHU Lille. Inserm LIRIC - UMR995, University of Lille, Lille, 59000, France.
ORCID: 0000-0003-3596-5497

Alexandre Louvet (A)

Service des Maladies de l'appareil digestif, CHU Lille. Inserm LIRIC - UMR995, University of Lille, Lille, 59000, France.

Gemma Odena (G)

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, NC, 27516, USA.

Juan L Gomez (JL)

Departments of Pathology and Medicine, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.

Tomas Aragon (T)

Department of Gene Therapy and Regulation, Center for Applied Medical Research, University of Navarra, Pamplona, 31008, Spain.

Jose Altamirano (J)

Liver Unit, Department of Internal Medicine, Vall d'Hebron Institut de Recerca. Internal Medicine Department, Hospital Quiron Salud, Barcelona, 08035, Spain.

Juan Caballeria (J)

Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.

Michael J Jurczak (MJ)

Department of Medicine, Division of Endocrinology and Metabolism, Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
ORCID: 0000-0002-6335-6915

D Lansing Taylor (DL)

University of Pittsburgh Drug Discovery Institute, Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Carmen Berasain (C)

Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, 31008, Spain.
Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain.
ORCID: 0000-0001-7075-2476

Claes Wahlestedt (C)

Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
ORCID: 0000-0003-4471-5916

Satdarshan P Monga (SP)

Departments of Pathology and Medicine, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
ORCID: 0000-0002-8437-3378

Marsha Y Morgan (MY)

UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, WC1E 6BT, UK.

Pau Sancho-Bru (P)

Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain.
ORCID: 0000-0001-5569-9259

Philippe Mathurin (P)

Service des Maladies de l'appareil digestif, CHU Lille. Inserm LIRIC - UMR995, University of Lille, Lille, 59000, France.

Shinji Furuya (S)

Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77845, USA.

Carolin Lackner (C)

Medical University of Graz, Institute of Pathology, Graz, 8036, Austria.

Ivan Rusyn (I)

Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77845, USA.

Vijay H Shah (VH)

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA.

Mark R Thursz (MR)

Division of Digestive Diseases, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.

Jelena Mann (J)

Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Matias A Avila (MA)

Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, 31008, Spain.
Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain.

Ramon Bataller (R)

Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15261, USA. bataller@pitt.edu.
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, NC, 27516, USA. bataller@pitt.edu.
ORCID: 0000-0001-6570-3557

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Eucaryotes › Animaux › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Cytodiagnostic › Biopsie › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Assemblage et désassemblage de la chromatine › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Troubles dus à des produits chimiques › Troubles dus à l'abus d'alcool › Maladies alcooliques du foie › Hépatite alcoolique › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs nucléaires hépatocytaires › Facteur nucléaire hépatocytaire HNF-4 › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Système digestif › Foie › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › Defective HNF4alpha-dependent gene expression...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › Facteur de croissance transformant bêta-1 › Defective HNF4alpha-dependent gene expression...