Upregulation of scavenger receptor class B type I expression by activation of FXR in hepatocyte
Upregulation of scavenger receptor class B type I expression by activation of FXR in hepatocyte
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通过激活肝细胞中的 FXR 上调 B 类清道夫受体 I 型表达
DOI：
10.1016/j.atherosclerosis.2010.09.016
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发表时间：
2010-12-01
期刊：
影响因子：
5.3
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Chao, Fan;Gong, Wei;He, Fengtian
目的：法尼醇X受体(FXR)是核受体超家族成员之一，通过调节胆固醇和甘油三酯的代谢和转运，在心血管疾病的发病机制中发挥重要作用。B型清道夫受体(SR-BI)是一种高密度脂蛋白受体，通过调节胆固醇的反向转运，在减少脂代谢相关的心血管疾病中发挥重要作用。最近的研究表明，SR-BI的表达被几种核受体上调。然而，FXR在SR-BI表达调控中的作用还不是很清楚。在本研究中，我们研究了FXR对肝细胞SR-BI的调节及其机制。方法和结果：FXR配体作用于人肝癌细胞株HepG2后，SR-BI在mRNA和蛋白水平均上调。报告分析表明，FXR的激活显著增强了SR-BI启动子的活性。电泳迁移率改变和染色质免疫沉淀分析表明，FXR通过与一个新的FXR元件(FXRE)-定向重复DNA基序DR8(-703AGGCCAcgtctag AGCTCA-684)结合来诱导SR-BI的表达。结论：FXR可直接上调肝细胞SR-BI的表达，DR8可能是参与SR-BI调节的一种新的FXRE。FXR可作为调控SR-BI在肝细胞中表达的新的分子靶点。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
Objective: The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been proposed to play an important role in the pathogenesis of cardiovascular diseases by regulating the metabolism and transport of cholesterol and triglyceride. Scavenger receptor class B type I (SR-BI), a high-density lipoprotein receptor, plays an important role in decreasing lipid metabolism-associated cardiovascular diseases by regulating reverse cholesterol transport. Recent studies have shown that SR-BI expression is upregulated by several nuclear receptors. However, the role of FXR in the regulation of SR-BI expression is not well known. In the present study, we investigate the regulation of SR-BI by FXR in hepatocyte and the corresponding mechanism.Methods and results: Treatment of human hepatoma cell line HepG2 with FXR ligands resulted in upregulation of SR-BI at the levels of both mRNA and protein. Reporter assays showed that activation of FXR significantly enhanced the SR-BI promoter activity. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that FXR induced SR-BI expression by binding to a novel FXR element (FXRE), a directed repeat DNA motif, DR8 (-703 AGGCCAcgttctagAGCTCA -684). The in vivo experiment demonstrated that gavaging mice with a natural ligand of FXR increased SR-BI expression in liver tissues.Conclusions: FXR can directly upregulate SR-BI expression in hepatocyte, and DR8 is a likely novel FXRE that is involved in SR-BI regulation. FXR may serve as a novel molecular target for manipulating SR-BI expression in hepatocyte. (C) 2010 Elsevier Ireland Ltd. All rights reserved.