Hepatocyte-specific YAP knockout exacerbates non-alcoholic steatohepatitis by upregulating PCSK9

Background and AimsNonalcoholic steatohepatitis (NASH) is a high unmet clinical need due to a growing worldwide epidemic but no licensed drugs to treat it thus far. Herein, we aimed to explore the function of a Yes-associated protein (YAP) and its underlying mechanism in the progression of NASH so as to seek its therapeutic target.MethodsWe built mouse NASH model adopting a methionine-choline deficient (MCD).Global YAP knockout mice were used to determine effect of YAP on NASH-related phenotypes. Hepatocyte-specific YAP knockout mice were introduced to further study the function of hepatocellular YAP in NASH development. Furthermore, clarifying detailed mechanisms underlying hepatocellular YAP-regulated NASH was carried out in hepatocyte-specific YAP knockout mice. Adeno-associated virus (AAVs)-mediated hepatocyte-specific YAP overexpression was used to observe the therapeutic efficacy in mice fed by the MCD diet.ResultsThe YAP-/- mice displayed mild hepatic steatosis but a dramatic exacerbation of hepatic inflammation and fibrosis after feeding the MCD for 4 weeks. However, the mice injected by AAV9-YAP overexpressing YAP exhibited an almost complete opposite phenotype. Furthermore, consistent with those of Global YAP knockout mice, MCD-fed hepatocyte-specific YAP knockout mice also exhibited favorable hepatic steatosis phenotype but exacerbated inflammation and fibrosis in liver. Conversely, hepatocyte-specific YAP or YAP (5S) overexpression led to an almost complete reversal of hepatic pathologies in Hepatocyte-specific YAP knockout mice challenged by the MCD. Mechanistically, hepatocyte-specific PCSK9 knockdown effectively reversed the NASH progression in Hepatocyte-specific YAP knockout mice, suggesting that hepatocellular YAP suppressed NASH-related major phenotypes via up-regulation of PCSK9. More specifically, AAV8-mediated YAP expression in the hepatocyte substantially improved NASH progression in miceConclusionCollectively, our findings demonstrated hepatocellular YAP mitigates NASH severity by increasing PCSK9 expression, indicating that hepatocellular YAP may be a promising target for management of NASH.