组成型雄甾烷受体(CAR,NR3I1)属于核受体超家族。据报道,CAR激动剂TCPOBOP诱导肝肿大,但潜在的机制仍然很大程度上未知。Yes相关蛋白(YAP)是器官大小的有效调节剂。本研究的目的是探讨YAP在CAR激活诱导的肝肿大和肝再生中的作用。在野生型(WT)小鼠中评估TCPOBOP诱导的CAR活化对肝肿大和肝再生的影响,肝脏特异性YAP缺陷小鼠,和部分肝切除术(PHx)小鼠。结果表明,TCPOBOP可以增加野生型小鼠和PHx小鼠的肝体重比。观察到中央静脉(CV)区域周围的肝细胞增大,同时,门静脉(PV)区域周围的KI67细胞数量增加证明了肝细胞的增殖。在TCPOBOP处理的小鼠中,YAP及其下游靶标的蛋白质水平上调,并且可以通过CAR激活诱导YAP易位。免疫共沉淀结果表明了CAR和YAP的潜在蛋白质-蛋白质相互作用。然而,在肝脏特异性YAP缺陷(Yap-/-)小鼠中仍然可以观察到CAR活化诱导的肝肿大。总之,CAR激活部分通过诱导YAP易位和与YAP信号通路相互作用促进肝肿大和肝再生,这为进一步理解CAR的生理功能提供了新的见解。
The constitutive androstane receptor (CAR, NR3I1) belongs to nuclear receptor superfamily. It was reported that CAR agonist TCPOBOP induces hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced hepatomegaly and liver regeneration. TCPOBOP-induced CAR activation on hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67+ cells around portal vein (PV) area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential protein-protein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient (Yap -/-) mice. In summary, CAR activation promotes hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.