Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes
Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes
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DOI：
10.1210/me.2004-0324
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发表时间：
2005-02-01
影响因子：
--
通讯作者：
Lee, JW
中科院分区：
文献类型：
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作者：
Lee, S;Lee, DK;Lee, JW
胰岛素诱导基因 1 (Insig-1) 及其同源物 Insig-2 编码密切相关的内质网蛋白，这些蛋白可阻断甾醇调节元件结合蛋白、膜结合转录因子的蛋白水解激活，从而激活动物细胞中胆固醇和脂肪酸的合成。 These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes.在此，我们在Insig-2基因的启动子区域鉴定了一个新的1α,25-二羟基维生素D3 [1,25-(OH)(2)D-3]反应元件，该元件特异性结合视黄醇X受体和维生素D受体(VDR)的异二聚体，并以1,25(OH)(2)D-3依赖性方式指导VDR介导的转录激活。有趣的是，已知 1,25-(OH)(2)D-3 可以直接抑制过氧化物酶体增殖物激活受体 γ2 蛋白的表达，并抑制 3T3-L1 前脂肪细胞和小鼠骨髓基质细胞的脂肪细胞分化。与 1,25-(OH)(2)D-3 的抗脂肪作用也可能涉及 Insig-2 上调的观点一致，我们发现 1,25(OH)(2)D-3 短暂但强烈地诱导 3T3-L1 细胞中 Insig-2 的表达。这种新颖的调节回路也可能在表达 VDR 的其他脂肪生成细胞类型中发挥重要作用，我们的结果总的来说表明 1,25-(OH)(2)D-3 和脂肪生成之间存在有趣的新联系。
Insulin-induced gene-1 (Insig-1) and its homolog Insig-2 encode closely related proteins of the endoplasmic reticulum that block proteolytic activation of sterol regulatory element binding proteins, membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes. Herein, we identified a novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)(2)D-3] response element in the promoter region of Insig-2 gene, which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25(OH)(2)D-3-dependent manner. Interestingly, 1,25-(OH)(2)D-3 is known to directly suppress the expression of peroxisome proliferator-activated receptor gamma2 protein and inhibits adipocyte differentiation of 3T3-L1 preadipocytes and murine bone marrow stromal cells. Consistent with an idea that the antiadipogenic action of 1,25-(OH)(2)D-3 may also involve up-regulation of Insig-2, we found that 1,25(OH)(2)D-3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR, and collectively our results suggest an intriguing, new linkage between 1,25-(OH)(2)D-3 and lipogenesis.