Yes‐Associated Protein in Hepatocytes Protects Against Early Alcohol‐Associated Liver Disease

ABSTRACT Background and Aims Alcohol‐associated liver disease (ALD) is a current unmet clinical challenge attributed to a lack of effective pharmacological therapy. Yes‐associated protein (YAP) is a transcriptional co‐activator and has been extensively investigated in liver diseases. However, the role of YAP in ALD is still unclear. Methods The early ALD mouse model was induced using a Gao‐binge diet. Furthermore, the function of hepatic YAP in ALD was investigated using YAP −/− mice, mice injected with an adeno‐associated virus (AAV) 9‐delivered saCas9/sgYAP system (AAV9‐saCas9/sgYAP), or YAP ΔHep mice fed the Gao‐binge diet. The mechanisms underlying hepatocellular YAP‐regulated ALD were further studied in the YAP ΔHep mice. The therapeutic efficacy of hepatocellular YAP expression was tested using AAV8‐delivered YAP overexpression in mice fed the Gao‐binge diet. Results In response to the Gao‐binge diet, whole‐body YAP deficiency exacerbated early ALD‐related phenotypes in mice, including hepatic steatosis and inflammatory response. Furthermore, the YAP ΔHep mice also exhibited aggravated ALD‐related phenotypes. However, hepatocyte‐specific YAP or YAP (5S) overexpression substantially reversed the disease progression in the YAP ΔHep mice. Mechanistically, hepatocellular YAP inhibited hepatic steatosis, inflammatory response and fibrosis through down‐regulating CD36. Furthermore, the oncostatin (OSM)–STAT3 axis was involved in YAP‐mediated regulation of CD36. Notably, we also found that AAV8‐Alb‐YAP effectively ameliorated the progression of early ALD in mice. Conclusion Hepatocellular YAP functions as a negative regulator of pathological changes by inhibiting the OSM‐STAT3‐CD36 pathway during early ALD, representing a potential therapeutic target for early ALD.