Liver international : official journal of the International Association for the Study of the Liver · 2025
Yes-Associated Protein in Hepatocytes Protects Against Early Alcohol-Associated Liver Disease.
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Zhang Xin, Yang Xinpu, Sun Xia, Qin Qiaohong, Hou Ying, Jia Min, Su Xingli, Chen Yulong
Аннотация
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 YAPΔHep mice fed the Gao-binge diet. The mechanisms underlying hepatocellular YAP-regulated ALD were further studied in the YAPΔHep 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 YAPΔHep mice also exhibited aggravated ALD-related phenotypes. However, hepatocyte-specific YAP or YAP (5S) overexpression substantially reversed the disease progression in the YAPΔHep 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.
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 YAPΔHep mice fed the Gao-binge diet. The mechanisms underlying hepatocellular YAP-regulated ALD were further studied in the YAPΔHep 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 YAPΔHep mice also exhibited aggravated ALD-related phenotypes. However, hepatocyte-specific YAP or YAP (5S) overexpression substantially reversed the disease progression in the YAPΔHep 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.