Original articles
Yue Gao, Shicheng Fan, Hua Li, Yiming Jiang, Xinpeng Yao, Shuguang Zhu, Xiao Yang, Ruimin Wang, Jianing Tian, Frank J. Gonzalez, Min Huang, Huichang Bi. Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 727-737

Constitutive androstane receptor induced-hepatomegaly and liver regeneration is partially via yes-associated protein activation
Yue Gaoa, Shicheng Fana, Hua Lib, Yiming Jianga, Xinpeng Yaoa, Shuguang Zhub, Xiao Yanga, Ruimin Wanga, Jianing Tiana, Frank J. Gonzalezc, Min Huanga, Huichang Bia
a Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
b Department of Hepatic Surgery, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China;
c Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Abstract:
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 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 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.
Key words:    Constitutive androstane receptor    Nuclear receptors    Hepatomegaly    Liver enlargement    Liver regeneration    Yes-associated protein    Proteine—protein interaction    Partial hepatectomy   
Received: 2020-06-10     Revised: 2020-09-09
DOI: 10.1016/j.apsb.2020.11.021
Funds: The work was 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), and the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant number: 2017B090903004, China).
Corresponding author: Min Huang, Huichang Bi     Email:bihchang@mail.sysu.edu.cn;huangmin@mail.sysu.edu.cn
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Yue Gao
Shicheng Fan
Hua Li
Yiming Jiang
Xinpeng Yao
Shuguang Zhu
Xiao Yang
Ruimin Wang
Jianing Tian
Frank J. Gonzalez
Min Huang
Huichang Bi

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