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

Josepmaria Argemi; Maria U Latasa; Stephen R Atkinson; Ilya O Blokhin; Veronica Massey; Joel P Gue; Joaquin Cabezas; Juan J Lozano; Derek Van Booven; Aaron Bell; Sheng Cao; Lawrence A Vernetti; Juan P Arab; Meritxell Ventura-Cots; Lia R Edmunds; Constantino Fondevilla; Peter Stärkel; Laurent Dubuquoy; Alexandre Louvet; Gemma Odena; Juan L Gomez; Tomas Aragon; Jose Altamirano; Juan Caballeria; Michael J Jurczak; D Lansing Taylor; Carmen Berasain; Claes Wahlestedt; Satdarshan P Monga; Marsha Y Morgan; Pau Sancho-Bru; Philippe Mathurin; Shinji Furuya; Carolin Lackner; Ivan Rusyn; Vijay H Shah; Mark R Thursz; Jelena Mann; Matias A Avila; Ramon Bataller

doi:10.1038/s41467-019-11004-3

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

Journal article

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

Josepmaria Argemi, Maria U Latasa, Stephen R Atkinson, Ilya O Blokhin, Veronica Massey, Joel P Gue, Joaquin Cabezas, Juan J Lozano, Derek Van Booven, Aaron Bell, …

Nature communications, Vol.10(1), pp.3126-19

Nature Communications

2019-07-16

DOI: https://doi.org/10.1038/s41467-019-11004-3

PMCID: PMC6635373

PMID: 31311938

Abstract

Life Sciences

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.100 Substance Abuse; 1.100.1013 Alcoholic Liver Disease
Web Of Science research areas: Biochemistry & Molecular Biology
ESI research areas: Clinical Medicine

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Title: Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Creators: Josepmaria Argemi - University of Pittsburgh
Maria U Latasa - Universidad de Navarra [Pamplona]
Stephen R Atkinson - Imperial College London
Ilya O Blokhin - University of Miami Leonard M. Miller School of Medicine
Veronica Massey - University of North Carolina [Chapel Hill]
Joel P Gue - University of Pittsburgh
Joaquin Cabezas - University of North Carolina [Chapel Hill]
Juan J Lozano - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
Derek Van Booven - University of Miami Leonard M. Miller School of Medicine
Aaron Bell - University of Pittsburgh School of Medicine
Sheng Cao - Mayo Clinic [Rochester]
Lawrence A Vernetti - University of Pittsburgh
Juan P Arab - Mayo Clinic [Rochester]
Meritxell Ventura-Cots - University of Pittsburgh
Lia R Edmunds - University of Pittsburgh
Constantino Fondevilla - University of Barcelona
Peter Stärkel - Université Catholique de Louvain
Laurent Dubuquoy - Lille Inflammation Research International Center - U 995
Alexandre Louvet - Lille Inflammation Research International Center - U 995
Gemma Odena - University of North Carolina [Chapel Hill]
Juan L Gomez - University of Pittsburgh
Tomas Aragon - Universidad de Navarra [Pamplona]
Jose Altamirano - Vall d'Hebron University Hospital [Barcelona]
Juan Caballeria - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
Michael J Jurczak - University of Pittsburgh
D Lansing Taylor - University of Pittsburgh
Carmen Berasain - Universidad de Navarra [Pamplona]
Claes Wahlestedt - University of Miami Leonard M. Miller School of Medicine
Satdarshan P Monga - University of Pittsburgh School of Medicine
Marsha Y Morgan - University College of London [London]
Pau Sancho-Bru - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Philippe Mathurin - Lille Inflammation Research International Center - U 995
Shinji Furuya - Texas A&M University [College Station]
Carolin Lackner - Medical University Graz
Ivan Rusyn - Texas A&M University [College Station]
Vijay H Shah - Mayo Clinic [Rochester]
Mark R Thursz - Imperial College London
Jelena Mann - Newcastle University [Newcastle]
Matias A Avila - Universidad de Navarra [Pamplona]
Ramon Bataller - University of North Carolina [Chapel Hill]
Publication Details: Nature communications, Vol.10(1), pp.3126-19
Series: Nature Communications
Publisher: Nature Publishing Group
Academic Unit: Miller School of Medicine; UMMG Dept of Psychiatry & Behavioral Sciences
Language: French
Resource Type: Journal article
PMID: 31311938
PMCID: PMC6635373
Record Identifier: 991031578521902976