Orphan nuclear hormone receptor Rev-erbα regulates the human apolipoprotein CIII promoter
Orphan nuclear hormone receptor Rev-erbα regulates the human apolipoprotein CIII promoter
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DOI：
10.1074/jbc.m203421200
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发表时间：
2002-07-26
影响因子：
4.8
通讯作者：
Rodríguez, JC
中科院分区：
文献类型：
--
作者：
Coste, H;Rodríguez, JC
载脂蛋白CIII（apoCIII）在血浆甘油三酯和残余脂蛋白代谢中起重要作用。由于高脂血症是冠状动脉疾病的独立危险因素，血浆中富含脂蛋白的残余脂蛋白的存在与动脉粥样硬化相关，因此大量研究工作集中在鉴定调节apoCIII基因表达的因子以减少其产生。在这里，我们报告说，孤儿核激素受体Rev-erbalpha调节人类apoCIII基因启动子。在表达apoCIII的人肝HepG 2细胞中，Rev-erba的转染特异性地抑制apoCIII基因启动子活性。我们通过缺失和定点突变实验确定，Rev-erba依赖性抑制主要是由于apoCIII基因近端启动子中存在的元件。相比之下，我们没有发现功能性Rev-erba反应元件在收敛转录的人apoAI基因或共同的调节增强子。已确定的Rev-erba响应元件与RORalpha 1元件一致，在本研究中，我们提供了这些孤儿受体之间的功能性串扰调节apoCIII启动子的证据。体外结合分析表明，Rev-erba的单体结合该元件，但不结合另一个上游RORalpha 1反应元件。此外，我们发现，密切相关的核孤儿受体RVR也特异性抑制人apoCIII基因。这些研究强调了一个新的生理作用的Rev-erb家族成员的核受体在调节基因参与甘油三酯代谢和动脉粥样硬化的发病机制。
Apolipoprotein CIII (apoCIII) plays an important role in plasma triglyceride and remnant lipoprotein metabolism. Because hypertriglyceridemia is an independent risk factor in coronary artery disease and the presence in plasma of triglyceride-rich remnant lipoproteins is correlated with atherosclerosis, considerable research efforts have been focused on the identification of factors regulating apoCIII gene expression to decrease its production. Here we report that the orphan nuclear hormone receptor Rev-erbalpha regulates the human apoCIII gene promoter. In apoCIII expressing human hepatic HepG2 cells, transfection of Rev-erba specifically repressed apoCIII gene promoter activity. We determined by deletion and site-directed mutagenesis experiments that Rev-erba dependent repression is mainly due to an element present in the proximal promoter of the apoCIII gene. In contrast, we found no functional Rev-erba response elements in the convergently transcribed human apoAI gene or the common regulatory enhancer. The identified Rev-erba response element coincides with a RORalpha1 element, and in the present study we provide evidence that functional cross-talk between these orphan receptors modulates the apoCIII promoter. In vitro binding analysis showed that monomers of Rev-erba bound this element but not another upstream RORalpha1 response element. In addition, we showed that the closely related nuclear orphan receptor RVR also specifically repressed the human apoCIII gene. These studies underscore a novel physiological role for members of the Rev-erb family of nuclear receptors in the regulation of genes involved in triglyceride metabolism and the pathogenesis of atherosclerosis.