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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.

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