- [HEPATIC DAMAGE AND CARCINOGENESIS]
- [GENE THERAPY AND REGULATION OF GENE EXPRESSION]
- [ENDOPLASMIC RETICULUM STRESS RESPONSE IN NEURODEGENERATIVE DISEASES]
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
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.