LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism.

Abstract

Long noncoding RNAs constitute a significant portion of the human genome. Among these, lncRNA H19, initially identified for its high expression during fetal development followed by a decline in the liver postnatally, re-emerges in various liver diseases. However, its specific role in alcohol-associated liver disease (ALD) remains unclear. Elevated H19 levels were detected in peripheral blood and livers of patients with alcohol-associated cirrhosis and hepatitis, as well as in livers of ethanol-fed mice. Hepatic overexpression of H19 exacerbated ethanol-induced liver steatosis and injury. Metabolomics analysis revealed decreased methionine levels in H19-overexpressed mouse livers, attributable to H19-mediated inhibition of betaine homocysteine methyltransferase (BHMT), a crucial enzyme in methionine synthesis. H19 regulated BHMT alternative splicing through polypyrimidine tract-binding protein 1 (PTBP1), resulting in a reduced Bhmt protein-coding variant. The maternally specific knockout of H19 (H19Mat+/-) or liver-specific knockout of the H19 differentially methylated domain (H19DMDHep-/-) in ethanol-fed mice upregulated BHMT expression and ameliorated hepatic steatosis. Furthermore, BHMT restoration counteracted H19-induced ethanol-mediated hepatic steatosis. This study identifies a novel mechanism whereby H19, via PTBP1-mediated BHMT regulation, influences methionine metabolism in ALD. Targeting the H19-PTBP1-BHMT pathway may offer new therapeutic avenues for ALD.