RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium.
RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium.
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DOI：
10.1161/circresaha.112.268110
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发表时间：
2012-09-28
影响因子：
20.1
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Messmer-Blust AF;Philbrick MJ;Guo S;Wu J;He P;Guo S;Li J
相关转录增强因子-1(RTEF-1)通过调节血管生成，在血管内皮细胞功能中发挥重要作用。然而，RTEF-1在活体内皮细胞中的作用机制尚不清楚。我们通过破坏编码RTEF-1的基因(RTEF-1-/-)来研究RTEF-1的生物学功能。RTEF-1-/-小鼠表现出显著的血糖水平和胰岛素抵抗，并伴有内皮细胞胰岛素样生长因子结合蛋白-1(IGFBP-1)mRNA水平的下降和血清IGFBP-1水平的下降。此外，当小鼠喂食高脂肪食物时，RTEF-1-/-表型加剧，与IGFBP-1水平降低相关。相比之下，高表达血管内皮细胞钙粘蛋白(VE-Cad)/RTEF-1的转基因小鼠表现出对高脂肪饮食的葡萄糖清除和胰岛素敏感性的改善。此外，我们还证明了RTEF-1通过选择性地结合和促进胰岛素反应元件(IRE)位点的转录来上调IGFBP-1。胰岛素以剂量依赖的方式抑制内皮细胞RTEF-1的表达，并显著抑制IGFBP-1的转录。据我们所知，这是第一个证明RTEF-1通过IRE元件刺激启动子活性并介导胰岛素对基因表达影响的报告。这些结果表明，RTEF-1刺激的IGFBP-1的表达可能是RTEF-1降低血糖水平的核心机制。这些发现为深入了解IGFBP-1的转录调控提供了新的基础，并有助于理解血管内皮细胞在代谢中的作用。
Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in endothelial cell function by regulating angiogenesis. However, the mechanism underlying the role of RTEF-1 in the endothelium in vivo is not well defined. We investigated the biological functions of RTEF-1 by disrupting the gene that encodes it in mice endothelium (RTEF-1-/-). RTEF-1-/- mice showed significantly increased blood glucose levels and insulin resistance, accompanied by decreased levels of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA in the endothelium and decreased serum IGFBP-1 levels. Additionally, the RTEF-1-/- phenotype was exacerbated when the mice were fed a high fat diet, correlating with decreased IGFBP-1 levels. In contrast, vascular endothelial-cadherin (VE-Cad)/RTEF-1 overexpressing transgenic mice demonstrated improved glucose clearance and insulin sensitivity in response to a high fat diet. Furthermore, we demonstrated that RTEF-1 up-regulates IGFBP-1 through selectively binding and promoting transcription from the insulin response element (IRE) site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion. To our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an IRE element and also mediates the effects of insulin on gene expression. These results show that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to understanding the role of vascular endothelial cells in metabolism.