Dysfunction of epithelial splicing regulator protein 2 promotes the initiation of MASH
Epithelial splicing regulator protein 2 (ESRP2) is a conservative splicing regulator that controls the maturation of the liver. However, the role of ESRP2 in the progression from metabolic dysfunction-associated liver simple steatosis to steatohepatitis (MASH) is uncertain. Here, we investigated the effects of gain or loss of ESRP2 function on the development of MASH and the underlying mechanism. In the high fat and high glucose with choline deficiency (HFG-CD) diet-induced mice model, overexpression of Esrp2 protected against hepatic steatosis, whereas loss of Esrp2 had opposite effects. By down-regulating YAP in AML-12 and HepG2 cells, overexpression of ESRP2 attenuated PA (palmitic acid)/OA (oleic acid)-induced lipid accumulation and elevated the levels of p-LATS1 to decrease the levels of YAP, whereas down-expression of ESRP2 had the contrary effects. Pathways of the lipid metabolic process and inflammation process significantly changed in the livers of HFG-CD-fed Esrp2 overexpressed mice. We conclude that elevated levels of Esrp2 alleviated HFG-CD-induced hepatic steatosis via regulating inflammation, lipid accumulation, and fibrosis. The underlying mechanism involves the inhibition of YAP by Esrp2 through alternative splicing. These findings suggest that Esrp2 plays an important role in the development of MASH.