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 Fondevila, 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 and Ramon Bataller ()
Additional contact information
Josepmaria Argemi: University of Pittsburgh Medical Center (UPMC)
Maria U. Latasa: University of Navarra
Stephen R. Atkinson: Imperial College London
Ilya O. Blokhin: University of Miami Miller School of Medicine
Veronica Massey: University of North Carolina at Chapel Hill
Joel P. Gue: University of Pittsburgh Medical Center (UPMC)
Joaquin Cabezas: University of North Carolina at Chapel Hill
Juan J. Lozano: Enfermedades Hepáticas y Digestivas (CIBERehd)
Derek Van Booven: University of Miami
Aaron Bell: University of Pittsburgh School of Medicine
Sheng Cao: Mayo Clinic
Lawrence A. Vernetti: University of Pittsburgh
Juan P. Arab: Mayo Clinic
Meritxell Ventura-Cots: University of Pittsburgh Medical Center (UPMC)
Lia R. Edmunds: University of Pittsburgh
Constantino Fondevila: University of Barcelona
Peter Stärkel: Université Catholique de Louvain
Laurent Dubuquoy: University of Lille
Alexandre Louvet: University of Lille
Gemma Odena: University of North Carolina at Chapel Hill
Juan L. Gomez: University of Pittsburgh School of Medicine
Tomas Aragon: University of Navarra
Jose Altamirano: Hospital Quiron Salud
Juan Caballeria: Enfermedades Hepáticas y Digestivas (CIBERehd)
Michael J. Jurczak: University of Pittsburgh
D. Lansing Taylor: University of Pittsburgh
Carmen Berasain: University of Navarra
Claes Wahlestedt: University of Miami Miller School of Medicine
Satdarshan P. Monga: University of Pittsburgh School of Medicine
Marsha Y. Morgan: University College London
Pau Sancho-Bru: Enfermedades Hepáticas y Digestivas (CIBERehd)
Philippe Mathurin: University of Lille
Shinji Furuya: Texas A&M University
Carolin Lackner: Institute of Pathology
Ivan Rusyn: Texas A&M University
Vijay H. Shah: Mayo Clinic
Mark R. Thursz: Imperial College London
Jelena Mann: Newcastle University
Matias A. Avila: University of Navarra
Ramon Bataller: University of Pittsburgh Medical Center (UPMC)

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11004-3

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