Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis [Suppl Data]

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 the development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). TGFb1is a key upstream transcriptome regulator in AH and induces the use of HNF4aP2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4aare 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 HNF4a-dependent gene expression. We conclude that targeting TGFb1and epigenetic drivers that modulate HNF4a-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.

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 the development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). TGFb1is a key upstream transcriptome regulator in AH and induces the use of HNF4aP2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4aare 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 HNF4a-dependent gene expression. We conclude that targeting TGFb1and epigenetic drivers that modulate HNF4a-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.