Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression
Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression
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DOI：
10.1016/s0016-5085(03)00896-5
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发表时间：
2003-08-01
期刊：
影响因子：
29.4
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Claudel, T;Inoue, Y;Staels, B
背景与目的：血清甘油三酯水平升高是冠心病的危险因素。载脂蛋白CIII （Apo CIII）是血清甘油三酯代谢的决定因素。在这项研究中，我们研究了核法氏体X受体（FXR）的激活剂是否调节Apo CIII基因的表达。方法：在体内采用FXR野生型和FXR缺陷小鼠，体外采用人原代肝细胞和HepG2细胞，研究胆汁酸和合成FXR激活剂对Apo CIII和甘油三酯代谢的影响。结果。在小鼠中，用FXR激动剂牛磺胆酸治疗可显著降低血清甘油三酯水平，这种作用与降低血清和肝脏信使RNA水平有关。相比之下，在fxr缺陷小鼠中没有观察到变化。人原代肝细胞和HepG2细胞与胆汁酸或非甾体合成FXR激动剂GW4064孵育后，Apo CIII基因表达呈剂量依赖性下调。启动子导入实验和突变分析表明，胆汁酸激活的FXR通过位于核苷酸-739和-704之间的14个足迹的负FXR响应元件降低人Apo CIII启动子活性。染色质免疫沉淀实验表明，胆汁酸处理导致FXR/类视黄醇X受体异源二聚体与该位点的结合和hnf4 α的位移。在肝脏hnf4 α缺陷小鼠中，胆红酸处理仍能抑制肝脏Apo CIII基因的表达，这表明FXR抑制Apo CIII的机制是主动的，而不是竞争性的。结论。我们发现胆汁酸和核FXR的合成激活剂是Apo CIII表达的负调节因子，这种作用可能有助于FXR激动剂降低甘油三酯的作用。
Background & Aims: Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression. Methods: The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells. Results. In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the 14 footprint between nucleotides -739 and -704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4alpha from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4alpha-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR. Conclusions. We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists.