Abstract：
Carbon tetrachloride (CCl4) has a wide range of toxic effects, especially causing acute liver injury (ALI), in which rapid compensation for hepatocyte loss ensures liver survival, but proliferation of surviving hepatocytes (known as endoreplication) may imply impaired residual function. Yes-associated protein (YAP) drives hepatocytes to undergo endoreplication and ploidy, the underlying mechanisms of which remain a mystery. In the present study, we uncover during CCl4-mediated ALI accompanied by increased hepatocytes proliferation and YAP activation. Notably, bioinformatics analyses elucidate that hepatic-specific deletion of YAP substantially ameliorated CCl4-induced hepatic proliferation, effectively decreased the vitamin D receptor (VDR) expression. Additionally, a mouse model of acute liver injury substantiated that inhibition of YAP could suppress hepatocytes proliferation via VDR. Furthermore, we also disclosed that the VDR agonist nullifies CCl4-induced ALI alleviated by the YAP inhibitor in vivo. Importantly, hepatocytes were isolated from mice, and it was spotlighted that the anti-proliferative impact of the YAP inhibitor was abolished by the activation of VDR within these hepatocytes. Similarly, primary hepatic stellate cells (HSCs) were isolated and it was manifested that YAP inhibitor suppressed HSC activation via VDR during acute liver injury. Our findings further elucidate the YAP\'s role in ALI and may provide new avenues for protection against CCl4-drived acute liver injury.
摘要：
四氯化碳(CCl4)具有广泛的毒性作用,尤其是引起急性肝损伤（ALI），其中快速补偿肝细胞损失确保肝脏存活，但存活肝细胞的增殖（称为内复制）可能意味着受损的残余功能。Yes相关蛋白（YAP）驱动肝细胞进行内复制和倍性，其潜在机制仍然是个谜。在本研究中,我们揭示了在CCl4介导的ALI期间伴随肝细胞增殖和YAP激活增加。值得注意的是,生物信息学分析阐明，YAP的肝特异性缺失实质上改善了CCl4诱导的肝增殖，能有效降低维生素D受体(VDR)的表达。此外,小鼠急性肝损伤模型证实抑制YAP可以通过VDR抑制肝细胞增殖。此外，我们还公开了VDR激动剂使由YAP抑制剂在体内减轻的CCl4诱导的ALI无效。重要的是,从小鼠中分离肝细胞，人们注意到YAP抑制剂的抗增殖作用被这些肝细胞内VDR的激活所消除。同样，分离原代肝星状细胞（HSC），表明YAP抑制剂在急性肝损伤期间通过VDR抑制HSC活化。我们的发现进一步阐明了YAP在ALI中的作用，并可能为防止CCl4引起的急性肝损伤提供新的途径。
