Farnesoid X receptor activates transcription of the phospholipid pump MDR3
Farnesoid X receptor activates transcription of the phospholipid pump MDR3
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DOI：
10.1074/jbc.m308321200
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发表时间：
2003-12-19
影响因子：
4.8
通讯作者：
Cui, JS
中科院分区：
文献类型：
--
作者：
Huang, L;Zhao, A;Cui, JS
人类多药耐药基因MDR 3编码一种P-糖蛋白，属于ATP结合盒转运蛋白家族（ABCB 4）。MDR 3是磷脂穿过肝细胞小管膜的关键转运蛋白，这一点由人MDR 3缺陷导致进行性家族性肝内胆汁淤积III型的事实证明。先前已经报道，MDR 3表达受激素、细胞应激和外源性物质调节。在这里，我们表明，MDR 3基因是反式激活的法尼醇X受体（FXR）通过直接结合FXR/维甲酸X受体α异二聚体的高度保守的反向重复元件（FXR反应元件）在远端启动子（-1970至-1958）。在FXR反式激活试验中，内源性FXR激动剂鹅脱氧胆酸盐和合成激动剂GW 4064都激活了MDR 3启动子。该反向重复元件的缺失或突变消除了FXR介导的MDR 3启动子激活。与这些数据一致，在原代人肝细胞中，鹅去氧胆酸盐和GW 4064均以时间和剂量依赖性方式显著诱导MDR 3 mRNA。总之，我们证明，MDR 3的表达是直接上调FXR。这些结果，连同先前关于胆盐输出泵是直接FXR靶点的报道，表明FXR协调控制胆盐和磷脂的分泌。这项研究的结果进一步支持了FXR是脂质代谢的主要调节剂的观点。
The human multidrug resistance gene MDR3 encodes a P-glycoprotein that belongs to the ATP-binding cassette transporter family (ABCB4). MDR3 is a critical trans-locator for phospholipids across canalicular membranes of hepatocytes, evidenced by the fact that human MDR3 deficiencies result in progressive familial intrahepatic cholestasis type III. It has been reported previously that MDR3 expression is modulated by hormones, cellular stress, and xenobiotics. Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958). In FXR trans-activation assays, both the endogenous FXR agonist chenodeoxycholate and the synthetic agonist GW4064 activated the MDR3 promoter. Deletion or mutation of this inverted repeat element abolished FXR-mediated MDR3 promoter activation. Consistent with these data, MDR3 mRNA was significantly induced by both chenodeoxycholate and GW4064 in primary human hepatocytes in time- and dose-dependent fashions. In conclusion, we demonstrate that MDR3 expression is directly up-regulated by FXR. These results, together with the previous report that the bile salt export pump is a direct FXR target, suggest that FXR coordinately controls secretion of bile salts and phospholipids. Results of this study further support the notion that FXR is a master regulator of lipid metabolism.