SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism
SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism
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SRC-3是CAR调节的肝细胞增殖和药物代谢所必需的
DOI：
10.1016/j.jhep.2011.07.015
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发表时间：
2012-01-01
影响因子：
25.7
通讯作者：
Yu, Chundong
中科院分区：
文献类型：
--
作者：
Chen, Tenghui;Chen, Qiang;Yu, Chundong
背景与目的：核受体如孕烷X受体和组成型雄烷受体（CAR）是P450酶等药物代谢系统的重要调节因子，并调节外源代谢和肝细胞增殖。CAR单独结合NR应答元件并不足以激活基因表达。在这里，我们研究类固醇受体共激活物（SRC）家族成员在car介导的肝细胞增殖和药物代谢中的作用。方法：通过细胞转染试验和蛋白-蛋白相互作用试验评估src在CAR活化中的作用。用src缺失的小鼠研究了src在car介导的肝细胞增殖和药物代谢中的体内作用。结果：在基于细胞的报告细胞实验中，与SRC-1和SRC-2相比，SRC-3对CAR的共激活活性最高。敲除SRC-3可以减轻CAR激动剂1,4-二-[2-（3,5-二氯吡啶氧基）]苯（TCPOBOP）诱导的小鼠肝增生，这与c-Myc和Foxm-1的表达降低有关。相反，敲除小鼠的SRC-1或SRC-2并不影响tcpobop诱导的肝脏增生。src -3缺陷小鼠对唑唑胺诱导的麻痹过敏，但对TCPOBOP诱导的对乙酰氨基酚肝毒性有抗性，而SRC-1或SRC-2缺陷的突变小鼠表现出与野生型对照组相似的严重对乙酰氨基酚肝毒性。因此，缺乏SRC-3，而不缺乏SRC-1或SRC-2，导致肝脏中car介导的药物代谢相关基因表达减少。结论：我们的研究表明SRC-3是SRC家族三种成员中主要的转录共激活因子，可激活CAR，促进肝细胞增殖和药物代谢。(C) 2011年欧洲肝脏研究协会。Elsevier B.V.版权所有。
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.