摘要
The constitutive androstane receptor(CAR, NR3 I1) 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 wildtype(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 hepatocytesproliferation 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 proteineprotein interaction of CAR and YAP. However, CAR activation-induced hepatomegaly can still be observed in liver-specific YAP-deficient(Yape/e) 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.
基金
supported by the Natural Science Foundation of China (Grant numbers:82025034 and 81973392)
the National Key Research and Development Program (Grant number:2017YFE0109900, China)
the Shenzhen Science and Technology Program (Grant number:KQTD20190929174023858, China)
the Natural Science Foundation of Guangdong (Grant number:2017A030311018, China)
the 111 project (Grant number:B16047, China)
the Key Laboratory Foundation of Guangdong Province (Grant number:2017B030314030, China)
the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant number:2017BT01Y093, China)
the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant number:2017B090903004, China)。
