Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation  

作　　者：Yue Gao Shicheng Fan Hua Li Yiming Jiang Xinpeng Yao Shuguang Zhu Xiao Yang Ruimin Wang Jianing Tian Frank JGonzalez Min Huang Huichang Bi 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]Department of Hepatic Surgery,the Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510006,China [3]Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,NIH,Bethesda,MD 20892,USA

出　　处：《Acta Pharmaceutica Sinica B》2021年第3期727-737,共11页药学学报（英文版）

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)。

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.

关 键 词：Constitutive androstane receptor Nuclear receptors HEPATOMEGALY Liver enlargement Liver regeneration Yes-associated protein Proteineprotein interaction Partial hepatectomy 

分 类 号：R575[医药卫生—消化系统]