Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids
Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids
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DOI：
10.1210/me.15.10.1720
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发表时间：
2001-10-01
影响因子：
--
通讯作者：
Edwards, PA
中科院分区：
文献类型：
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作者：
Kast, HR;Nguyen, CM;Edwards, PA
法尼醇X激活受体（FXR; NR 1H 4）是核激素受体超家族的一员，可诱导基因表达以响应包括鹅去氧胆酸在内的几种胆汁酸。在这里，我们使用抑制消减杂交，以确定载脂蛋白C-II（apoC-II）作为FXR的靶基因。FXR在HepG 2细胞中的逆转录病毒表达导致编码apoC-II的mRNA响应于几种FXR配体的诱导。EMSA证实重组FXR和RXR结合两个FXR应答元件，所述两个FXR应答元件包含在位于apoC-II基因转录起始位点上游11 kb和22 kb的两个重要远端增强子元件（肝控制区）内。当用FXR配体处理含有FXR的细胞时，含有肝脏控制区或两个野生型FXR反应元件拷贝的荧光素酶报告基因被激活。此外，我们报告说，肝脏表达的apoC-II和磷脂转移蛋白的mRNA增加时，小鼠饲料中补充胆酸，FXR配体，这种诱导减弱FXR空小鼠。最后，我们观察到喂食含胆酸饮食的小鼠血浆甘油三酯水平降低。这些结果确定了FXR及其配体降低血浆甘油三酯水平的机制。这些发现可能对高血压的临床治疗有重要意义。
The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid-containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias.