Regulation of insulin-response element binding protein-1 in obesity and diabetes: Potential role in impaired insulin-induced gene transcription
Regulation of insulin-response element binding protein-1 in obesity and diabetes: Potential role in impaired insulin-induced gene transcription
复制标题
DOI：
10.1210/en.2007-1693
复制
发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Villafuerte, Betty C.
中科院分区：
文献类型：
--
作者：
Chahal, Jaspreet;Chen, Ching-Chu;Villafuerte, Betty C.
胰岛素调节葡萄糖稳态的主要机制之一是通过调节基因表达。因此，胰岛素调节基因表达所需的转录因子表达减少可能导致胰岛素抵抗。我们最近发现胰岛素反应元件结合蛋白-1（IRE-BP 1）是一种结合并反式激活多个胰岛素反应基因的转录因子，但IRE-BP 1的体内调节在很大程度上尚不清楚。在这项研究中，我们表明，IRE-BP 1与IGF-I，IGFBP-1和IGFBP-3基因的胰岛素反应序列相互作用，使用染色质免疫沉淀法。此外，IRE-BP 1的激活是序列特异性的，并模拟胰岛素对基因转录的影响。与非靶组织相比，瘦动物中经典胰岛素靶组织中IRE-BP 1的组织表达高50至200倍，肥胖和糖尿病动物中骨骼肌和脂肪组织中的表达水平显著降低。在肝脏中，IRE-BP 1定位于瘦大鼠的细胞核，但在肥胖和糖尿病动物中被隔离到细胞质。细胞质隔离似乎与胰岛素介导的磷脂酰肌醇-3激酶信号传导的抑制有关。因此，在糖尿病和肥胖症中，通过IRE-BP 1降低胰岛素应答序列的反式激活所涉及的机制包括降低基因转录和核排斥以防止DNA结合。我们的研究支持了IRE-BP 1可能与体内胰岛素的作用有关的观点，并可能在胰岛素抵抗和糖尿病的发展中发挥作用。
One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.