Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
Atherosclerosis. 2010 Dec;213(2):443-8. doi: 10.1016/j.atherosclerosis.2010.09.016. Epub 2010 Oct 16.
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.
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.
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.
法尼醇 X 受体（FXR）是核受体超家族的成员，据推测其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。清道夫受体 B 类 I 型（SR-BI）是一种高密度脂蛋白受体，通过调节胆固醇的逆向转运，在降低与脂质代谢相关的心血管疾病方面发挥重要作用。最近的研究表明，几种核受体上调了 SR-BI 的表达。然而，FXR 调节 SR-BI 表达的作用尚不清楚。在本研究中，我们研究了 FXR 在肝细胞中对 SR-BI 的调节及其相应的机制。
用 FXR 配体处理人肝癌细胞系 HepG2 可使 SR-BI 的 mRNA 和蛋白水平均上调。报告基因检测表明，FXR 的激活显著增强了 SR-BI 启动子活性。电泳迁移率变动分析和染色质免疫沉淀分析表明，FXR 通过结合一个新的 FXR 元件（FXRE），即一个定向重复 DNA 基序 DR8（-703 AGGCCAcgttctagAGCTCA-684），诱导 SR-BI 的表达。体内实验表明，用 FXR 的天然配体灌胃小鼠可增加肝脏组织中 SR-BI 的表达。
FXR 可直接上调肝细胞中 SR-BI 的表达，而 DR8 可能是一个新的 FXRE，参与 SR-BI 的调节。FXR 可能成为一种操纵肝细胞中 SR-BI 表达的新的分子靶点。
