Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Keywords: 
Materias Investigacion::Ciencias de la Salud::Hepatología
Issue Date: 
2019
Publisher: 
Springer Science and Business Media LLC
ISSN: 
2041-1723
Note: 
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Citation: 
Argemí, J. (Josepmaria); Latasa, M.U. (María Ujué); Atkinson, S.R. (Stephen R.); et al. "Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis". Nature Communications. 10 (3126), 2019, 1 - 19
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.

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