Yes-associated protein in hepatocytes protects against early alcohol-associated liver disease

Background and AimsAlcohol-associated liver disease (ALD) is a current unmet clinical challenge attributed to lack of therapeutic targets. Yes-associated protein (YAP) is has been extensively investigated in liver diseases, However, the role of YAP in ALD is still unclear.MethodsWe observed the expression of YAP in liver of mice with early ALD induced by a Gao-binge diet. The function of hepatic YAP in ALD was investigated using whole body YAP knockout mice, mice injected with an AAV9 saCas9 sgYAP, or hepatocyte specific YAP knockout mice fed by the Gao binge diet. The mechanisms underlying hepatocellular YAP regulated ALD were study in the hepatocyte specific YAP knockout mice. The therapeutic efficacy of hepatocellular YAP expression was tested using AAV8 delivered YAP overexpression in hepatocyte in mice fed with the Gao binge diet.ResultsYAP expression was significantly decreased in the liver of mice with early ALD.Whole body YAP deficiency exacerbated early ALD related phenotypes in mice, including hepatic steatosis and inflammatory response, as evidenced by that of the whole body YAP knockout mice or mice injected by AAV9 saCas9 sgYAP after feeding the Gao-binge diet. Furthermore, the hepatocyte specific YAP knockout mice also exhibited aggravated ALD related phenotypes. However, hepatocyte specific YAP or YAP (5S) overexpression substantially reversed the progression of the disease in the hepatocyte specific YAP knockout mice. Mechanistically, hepatocellular YAP inhibited hepatic steatosis and inflammation through down regulating CD36 signaling. Notably, we also found that AAV8 Alb YAP effectively ameliorated progression of early ALD in mice.ConclusionHepatocellular YAP functions as a negative regulator of pathological changes depending on inhibition of CD36 expression during early ALD, which represents a potential therapeutic target for early ALD.