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.