Hepatocyte-specific yes-associated protein knockout exacerbates non-alcoholic steatohepatitis by upregulating PCSK9

No licensed drugs have been established for the treatment of nonalcoholic steatohepatitis (NASH). Therefore, we aimed to explore the effect of Yes-associated protein (YAP) on NASH to provide a therapeutic target.

We constructed a mouse model of NASH, consuming either a methionine-choline deficient (MCD) or Gubra Amylin NASH (GAN) diet. Hepatocyte-specific YAP knockout (YAP^ΔHep) mice were introduced to investigate the function of hepatocyte YAP in NASH. Furthermore, detailed mechanisms were clarified using AML12 cells. Adeno-associated virus (AAV)-mediated hepatocyte YAP overexpression was used to observe the therapeutic efficacy in mice with NASH.

Hepatic YAP protein levels were increased in NASH models. The YAP deletion reduced hepatic steatosis and exacerbated hepatic inflammation and fibrosis. However, YAP overexpression leads to the opposite NASH phenotype. Furthermore, the MCD or GAN diet-fed YAP^ΔHep mice also exhibited a favorable hepatic steatosis phenotype with exacerbated inflammation and fibrosis in the liver. Conversely, hepatocyte-specific YAP or YAP (5S) overexpression led to an almost complete reversal of hepatic pathologies. Mechanistically, hepatocyte-specific PCSK9 knockdown effectively reversed NASH progression in YAP^ΔHep mice. Furthermore, the oncostatin M (OSM)-JAK2-STAT3 axis was involved in the YAP-mediated regulation of PCSK9. Notably, AAV8-mediated YAP overexpression in the hepatocyte improved NASH in mice.

Our findings demonstrate that hepatocyte YAP mitigates NASH severity by increasing PCSK9 expression via the OSM-JAK2-STAT3 pathway independent of lipid accumulation. Therefore, hepatocyte YAP may be a promising target for the management of NASH.