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Constitutive androstane receptor promoted- hepatomegaly and liver regeneration is partially via yes-associated protein activation
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  • Huichang BI,
  • Yue Gao,
  • Shicheng Fan,
  • Hua Li,
  • Yiming Jiang,
  • Xinpeng Yao,
  • Shuguang Zhu,
  • Xiao Yang,
  • Ruimin Wang,
  • Jianing Tian,
  • Frank Gonzalez,
  • Min Huang
Huichang BI
School of Pharmaceutical Sciences, Sun Yat-sen University
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Yue Gao
School of Pharmaceutical Sciences, Sun Yat-sen University
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Shicheng Fan
School of Pharmaceutical Sciences, Sun Yat-sen University
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Hua Li
Department of Hepatic Surgery, the Third Affiliated Hospital, Sun Yat-Sen University
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Yiming Jiang
School of Pharmaceutical Sciences, Sun Yat-sen University
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Xinpeng Yao
School of Pharmaceutical Sciences, Sun Yat-sen University
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Shuguang Zhu
Department of Hepatic Surgery, the Third Affiliated Hospital, Sun Yat-Sen University
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Xiao Yang
School of Pharmaceutical Sciences, Sun Yat-sen University
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Ruimin Wang
School of Pharmaceutical Sciences, Sun Yat-sen University
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Jianing Tian
School of Pharmaceutical Sciences, Sun Yat-sen University
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Frank Gonzalez
National Cancer Institute, National Institutes of Health
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Min Huang
Institute of Clinical Pharmacology
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Abstract

Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.

Peer review status:POSTED

28 Apr 2020Submitted to British Journal of Pharmacology
29 Apr 2020Assigned to Editor
29 Apr 2020Submission Checks Completed