Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding
Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding
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DOI：
10.1074/jbc.m208312200
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发表时间：
2003-03-21
影响因子：
4.8
通讯作者：
Mukherjee, R
中科院分区：
文献类型：
--
作者：
Kassam, A;Miao, B;Mukherjee, R
胆盐输出泵（BSEP）通过调节胆汁酸的小管排泄在脂质稳态中发挥着不可或缺的作用。BSEP基因表达的诱导由法尼醇X受体（FXR）介导，FXR作为异源二聚体与维甲酸X受体（RXR）结合至位于BSEP基因上游的FXR反应元件（FXRE）。RXR配体模拟几种配偶体配体，并在共同给药时显示出累加效应。使用实时定量PCR和共转染报告分析，我们证明，RXR激动剂LG 100268拮抗诱导BSEP表达的内源性和合成的FXR配体，CDCA和GW 4064，分别介导。此外，这种拮抗作用是RXR激动剂的一般特征，并且归因于FXR/RXR异二聚体与BSEP-FXRE结合的减少，以及RXR激动剂不能募集FXF/RXR的共激活剂。我们的数据表明，FXR/RXR是一种条件允许的异二聚体，是第一个RXR配体介导的FXR活性拮抗作用的例子。由于FXR激动剂降低甘油三酯水平，我们的研究结果表明，在啮齿动物和人类中，RXR激动剂在高甘油三酯血症的发生中观察到RXR介导的FXR活性拮抗作用具有新的作用。
The bile salt export pump (BSEP) plays an integral role in lipid homeostasis by regulating the canalicular excretion of bile acids. Induction of BSEP gene expression is mediated by the farnesoid X receptor (FXR), which binds as a heterodimer with the retinoid X receptor (RXR) to the FXR response element (FXRE) located upstream of the BSEP gene. RXR ligands mimic several partner ligands and show additive effects upon coadministration. Using real-time quantitative PCR and cotransfection reporter assays, we demonstrate that the RXR agonist LG100268 antagonizes induction of BSEP expression mediated by endogenous and synthetic FXR ligands, CDCA and GW4064, respectively. Moreover, this antagonism is a general feature of RXR agonists and is attributed to a decrease in binding of FXR/RXR heterodimers to the BSEP-FXRE coupled with the inability of RXR agonists to recruit coactivators to FXF/RXR. Our data suggest that FXR/RXR is a conditionally permissive heterodimer and is the first example of RXR ligand-mediated antagonism of FXR activity. Because FXR agonists lower triglyceride levels, our results suggest a novel role for RXR-mediated antagonism of FXR activity in the development of hypertriglyceridemia observed with RXR agonists in rodents and humans.