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
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
Author description:
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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

1. Konno Y, Negishi M, Kodama S. The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug Metabol Pharmacokinet 2008;23:8-13.
2. Willson TM, Kliewer SA. PXR, CAR and drug metabolism. Nat Rev Drug Discov 2002;1:259-66.
3. Kodama S, Negishi M. Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car. Drug Metab Rev 2006;38: 75-87.
4. Wei P, Zhang J, Egan-Hafley M, Liang SG, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 2000;407:920-3.
5. Lv C, Huang L. Xenobiotic receptors in mediating the effect of sepsis on drug metabolism. Acta Pharm Sin B 2020;10:33-41.
6. Sugatani J, Yamakawa K, Yoshinari K, Machida T, Takagi H, Mori M, et al. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem Biophys Res Commun 2002;292:492-7.
7. Eloranta JJ, Kullak-Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 2005;433:397-412.
8. Kachaylo EM, Pustylnyak VO, Lyakhovich VV, Gulyaeva LF. Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry (Mosc) 2011;76:1087-97.
9. Dash AK, Yende AS, Kumar S, Singh SK, Kotiya D, Rana M, et al. The constitutive androstane receptor (CAR): A nuclear receptor in health and disease. J Endocrinol Reprod 2014;18:59-74.
10. Qatanani M, Moore DD. CAR, the continuously advancing receptor, in drug metabolism and disease. Curr Drug Metabol 2005;6:329-39.
11. Costa RH, Kalinchenko VV, Tan YJ, Wang IC. The CAR nuclear receptor and hepatocyte proliferation. Hepatology 2005;42:1004-8.
12. Tschuor C, Kachaylo E, Limani P, Raptis DA, Linecker M, Tian Y, et al. Constitutive androstane receptor (CAR)-driven regeneration protects liver from failure following tissue loss. J Hepatol 2016;65: 66-74.
13. Blanco-Bose WE, Murphy MJ, Ehninger A, Offner S, Dubey C, Huang W, et al. C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia. Hepatology 2008;48:1302-11.
14. Ganzenberg K, Singh Y, Braeuning A. The time point of beta-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor. Toxicology 2013; 308:113-21.
15. Bhushan B, Stoops JW, Mars WM, Orr A, Bowen WC, Paranjpe S, et al. TCPOBOP-induced hepatomegaly and hepatocyte proliferation are attenuated by combined disruption of MET and EGFR signaling. Hepatology 2019;69:1702-18.
16. Kowalik MA, Saliba C, Pibiri M, Perra A, Ledda-Columbano GM, Sarotto I, et al. Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice. Hepatology 2011;53:2086-96.
17. Patel SH, Camargo FD, Yimlamai D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 2017;152:533-45.
18. Zhao C, Zeng C, Ye S, Dai X, He Q, Yang B, et al. Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ): A nexus between hypoxia and cancer. Acta Pharm Sin B 2020;10:947-60.
19. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 2007;17:2054-60.
20. Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci U S A 2010;107:1431-6.
21. Oh SH, Swiderska-Syn M, Jewell ML, Premont RT, Diehl AM. Liver regeneration requires Yap1-TGFb-dependent epithelial-mesenchymal transition in hepatocytes. J Hepatol 2018;69:359-67.
22. Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med 2016;8:352ra108.
23. Abe T, Amaike Y, Shizu R, Takahashi M, Kano M, Hosaka T, et al. Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes. Toxicol Sci 2018;165:408-19.
24. Jiang Y, Feng D, Ma X, Fan S, Gao Y, Fu K, et al. Pregnane X receptor regulates liver size and liver cell fate by Yes-associated protein activation in mice. Hepatology 2019;69:343-58.
25. Min G, Kim H, Bae Y, Petz L, Kemper JK. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J Biol Chem 2002;277:34626-33.
26. Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev 1989;69:708-64.
27. Chai X, Zeng S, Xie W. Nuclear receptors PXR and CAR: Implications for drug metabolism regulation, pharmacogenomics and beyond. Expet Opin Drug Metabol Toxicol 2013;9:253-66.
28. Li ZQ, Ding W, Sun SJ, Li J, Pan J, Zhao C, et al. Cyr61/CCN1 is regulated by Wnt/beta-Catenin signaling and plays an important role in the progression of hepatocellular carcinoma. PLoS One 2012;7: e35754.
29. Deng YZ, Chen PP, Wang Y, Yin D, Koeffler HP, Li BJ, et al. Connective tissue growth factor is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenicity through beta-catenin-Tcell factor/Lef signaling. J Biol Chem 2007;282:36571-81.
30. Luo Q, Kang Q, Si WK, Jiang W, Park JK, Peng Y, et al. Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells. J Biol Chem 2004;279:55958-68.
31. Kojic S, Nestorovic A, Rakicevic L, Belgrano A, Stankovic M, Divac A, et al. A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein. Arch Biochem Biophys 2010;502:60-7.
32. Labbe E, Lock L, Letamendia A, Gorska AE, Gryfe R, Gallinger S, et al. Transcriptional cooperation between the transforming growth factor-beta and wnt pathways in mammary and intestinal tumorigenesis. Cancer Res 2007;67:75-84.
33. Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li TS, et al. Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 1999; 97:767-77.
34. Mao SA, Glorioso JM, Nyberg SL. Liver regeneration. Transl Res 2014;163:352-62.
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