Drak2 Aggravates Nonalcoholic Fatty Liver Disease Progression Through SRSF6-Associated RNA Alternative Splicing

Abstract

Nonalcoholic hepatosteatosis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we revealed death-associated protein kinase-related apoptosis-inducing kinase-2(Drak2) is markedly upregulated in the livers of both patients and NAFLD/NASH diets-fed mice. Hepatic deletion of Drak2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome, indicated a crucial role of Drak2 in RNA splicing, and identified the splicing factor SRSF6 as a direct binding protein of Drak2. Further studies demonstrated that the binding of Drak2 inhibits phosphorylation of SRSF6 by the SRSF kinase(SRPK1) and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an indispensable role of Drak2 in NAFLD/NASH and offer a potential therapeutic target for this disease.