Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia
Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia
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DOI：
10.1172/jci118324
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发表时间：
1995-12-01
影响因子：
15.9
通讯作者：
Leff, T
中科院分区：
文献类型：
--
作者：
Li, WW;Dammerman, MM;Leff, T
血浆载脂蛋白CIII的过表达人载脂蛋白C Ⅲ启动子的一种遗传变异形式，含有5个单碱基对的变化，已被证明与患者群体中的严重高脂血症有关。在动物和培养细胞中，载脂蛋白C Ⅲ基因被胰岛素转录下调。在这项研究中，我们证明，与野生型启动子不同，变体启动子在其对胰岛素处理的应答中是缺陷的，在所有浓度的胰岛素下保持组成型活性。胰岛素调节的丧失定位于-482和-455处的多态性位点，其落入先前鉴定的胰岛素应答元件内，胰岛素调节的丧失可导致载脂蛋白C Ⅲ基因的过度表达，并促进高脂血症的发展。变体apo CIII启动子在人群中很常见，可能是高脂血症发生的主要促成因素。
Overexpression of plasma apolipoprotein CIII (ape CIII) causes hypertriglyceridemia in transgenic mice, A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population, In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin, In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin, The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element, Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia.