SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism

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	SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism
	Chen, Tenghui ; Chen, Qiang ; Xu, Yixiang ; Zhou, Qiling ; Zhu, Jingwei ; Zhang, Hao ; Wu, Qiao ; Xu, Jianming ; Yu, Chundong ; Yu CD(俞春东)
刊名	http://dx.doi.org/10.1016/j.jhep.2011.07.015
	2012-01
关键词	CONSTITUTIVE ANDROSTANE RECEPTOR NUCLEAR RECEPTOR IN-VIVO TRANSCRIPTIONAL COACTIVATOR LIVER HYPERPLASIA MITOGEN TCPOBOP INDUCTION FAMILY MICE HEPATOTOXICITY
英文摘要	National Basic Research Program of China (973 Program) [2009CB522200]; Natural Science Foundation of Fujian Province of China [2008J0110, 2010J06014]; Fundamental Research Funds for the Central Universities [2010121085]; Doctoral Program of Higher Education of China [20100121110004]; Science Planning Program of Fujian Province [2009J1010]; National Institutes of Health, United States of America [R01 DK058242]; Background & Aims: Nuclear receptors such as pregnane X receptor and constitutive androstane receptor (CAR) are important regulators of drug-metabolizing systems such as P450 enzymes and modulate xenobiotic metabolism as well as hepatocellular proliferation. Binding of CAR to NR response elements alone is not sufficient to activate gene expression. Here, we investigate the role of steroid receptor co-activator (SRC) family members in CAR-mediated hepatocyte proliferation and drug metabolism. Methods: The role of SRCs in CAR activation was assessed in cell-based transfection assays and protein-protein interaction assays. The in vivo role of SRCs in CAR-mediated hepatocyte proliferation and drug metabolism was examined by using mice deficient in SRCs. Results: SRC-3 displayed the highest co-activating activity to CAR compared with SRC-1 and SRC-2 in a cell-based reporter assay. Knockout of SRC-3 in mice attenuated hepatic hyperplasia induced by a CAR agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), which was associated with a reduced expression of c-Myc and Foxm-1. In contrast, knockout of SRC-1 or SRC-2 in mice did not affect TCPOBOP-induced hepatic hyperplasia. SRC-3-deficient mice were hypersensitive to zoxazolamine-induced paralysis, but were resistant to acetaminophen hepatotoxicity induced by TCPOBOP, whereas mutant mice deficient in SRC-1 or SRC-2 exhibited severe acetaminophen hepatotoxicity similar to wild-type controls. Accordingly, deficiency in SRC-3, but not SRC-1 or SRC-2, resulted in a reduced CAR-mediated expression of drug metabolism-related genes in the liver. Conclusions: Our study demonstrates that SRC-3 is the predominant transcriptional co-activator among the three SRC family members for CAR activation to promote hepatocyte proliferation and drug metabolism. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
语种	英语
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/64975]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Chen, Tenghui,Chen, Qiang,Xu, Yixiang,et al. SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism[J]. http://dx.doi.org/10.1016/j.jhep.2011.07.015,2012.
APA	Chen, Tenghui.,Chen, Qiang.,Xu, Yixiang.,Zhou, Qiling.,Zhu, Jingwei.,...&俞春东.(2012).SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism.http://dx.doi.org/10.1016/j.jhep.2011.07.015.
MLA	Chen, Tenghui,et al."SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism".http://dx.doi.org/10.1016/j.jhep.2011.07.015 (2012).