Inhibition of histone-lysine N-methyltransferase G9a exacerbates alcoholic steatohepatitis (ASH) in mice.

Abstract

Alcoholic steatohepatitis (ASH) is characterized by hepatic steatosis, inflammation, and alcohol-induced liver damage in humans. G9a, a histone methyltransferase, serves as a multipotent regulator of gene expression and plays a significant role in hepatic drug metabolism and cellular stress. Although epigenetic alterations occur during alcoholic liver disease progression, G9a's precise contribution to ASH pathogenesis remains unclear. Using a murine model of ASH, we demonstrate that G9a expression is downregulated during ASH progression, and G9a pharmacological inhibition exacerbates ASH severity, shown by increased hepatic steatosis and serum ALT levels. Through an integrated transcriptomic and metabolomic approach, we show that loss of G9a activity in alcohol-exposed mice enhances hepatic expression of gene sets involved in cell cycle, cytoskeletal rearrangement, steroid biosynthesis, cellular stress, and proinflammatory pathways. Liver metabolomic analysis revealed that G9a inhibition increased nucleotide degradation, hepatic choline depletion, and enhanced branched-chain amino acid (BCAA) synthesis. These results suggest that G9a repression, through its effect on nucleotide, choline, and BCAA metabolism, blunts liver regenerative potential despite a repair commitment to alcohol, leading to increased hepatic toxicity and aggravated ASH phenotype. This study highlights G9a's critical role in modulating hepatic susceptibility to alcohol toxicity.