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

Lookup NU author(s): Professor Jelena Mann

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Abstract

© 2019, The Author(s).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.

Publication metadata

Author(s): Argemi J, Latasa MU, Atkinson SR, Blokhin IO, Massey V, Gue JP, Cabezas J, Lozano JJ, Van Booven D, Bell A, Cao S, Vernetti LA, Arab JP, Ventura-Cots M, Edmunds LR, Fondevilla C, Starkel P, Dubuquoy L, Louvet A, Odena G, Gomez JL, Aragon T, Altamirano J, Caballeria J, Jurczak MJ, Taylor DL, Berasain C, Wahlestedt C, Monga SP, Morgan MY, Sancho-Bru P, Mathurin P, Furuya S, Lackner C, Rusyn I, Shah VH, Thursz MR, Mann J, Avila MA, Bataller R

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2019

Volume: 10

Issue: 1

Online publication date: 16/07/2019

Acceptance date: 10/06/2019

Date deposited: 13/09/2019

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

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

DOI: 10.1038/s41467-019-11004-3

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