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

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-11004-3

2041-1723

Josepmaría Argemí, María U. Latasa, Stephen R. Atkinson, Ilya O. Blokhin, Veronica Massey, Joel P. Gue, Joaquín Cabezas, Juan José Lozano, Derek Van Booven, Aaron Bell, Sheng Cao, Lawrence A. Vernetti, Juan Pablo Arab, Meritxell Ventura‐Cots, Lia R. Edmunds, Constantino Fondevila, Peter Stärkel, Laurent Dubuquoy, Alexandre Louvet, Gemma Òdena, Juan L. Gómez, Tomás Aragón, José Altamirano, Juan Caballería, 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 Thursz, Jelena Mann, Matías A. Ávila, Ramón Bataller,

Peroxisome Proliferator-Activated Receptors

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). TGF β 1 is a key upstream transcriptome regulator in AH and induces the use of HNF4 α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4 α 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 HNF4 α -dependent gene expression. We conclude that targeting TGF β 1 and epigenetic drivers that modulate HNF4 α -dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.