miR-200a regulates Rheb-mediated amelioration of insulin resistance after duodenal-jejunal bypass.
miR-200a regulates Rheb-mediated amelioration of insulin resistance after duodenal-jejunal bypass.
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miR-200a 调节十二指肠空肠旁路术后 Rheb 介导的胰岛素抵抗改善
DOI：
10.1038/ijo.2016.60
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Hu S
中科院分区：
文献类型：
--
作者：
Guo W;Han H;Wang Y;Zhang X;Liu S;Zhang G;Hu S
十二指肠空肠旁路（DJB）手术可以诱导糖尿病快速而持久的缓解。最近的研究表明，肝脏胰岛素抵抗的改善和胰岛素信号传导的改善可能有助于 DJB 后观察到的糖尿病控制。据报道，大脑中富集的 Ras 同源物 (Rheb) 在胰岛素途径中具有重要作用，并且已发现一些 microRNA (miRNA) 可以调节 Rheb。本研究旨在研究 DJB 对肝脏胰岛素抵抗的影响，以及 miRNA-200a（一种 Rheb 靶向 miRNA）对 DJB 诱导的肝脏胰岛素抵抗改善的影响。我们研究了肝脏胰岛素信号传导的变化，并绘制了 DJB 大鼠模型中涉及的肝脏 miRNA 组图。我们研究了 miR-200a 对水牛大鼠肝细胞系中 Rheb 信号通路的影响。研究人员对注射了编码 miR-200a 抑制剂的慢病毒的 DJB 大鼠和注射了 miR-200a 模拟物的糖尿病大鼠进行了肝组织研究并进行了葡萄糖耐量测试。 Rheb 是 miR-200a 的潜在靶标。转染 miR-200a 抑制剂可增加 Rheb 蛋白水平，并增强对胰岛素受体底物依赖性胰岛素信号传导的反馈作用，而转染 miR-200a 模拟物则产生相反的效果。荧光素酶测定证实 miR-200a 与 Rheb 的 3'UTR（非翻译区）结合。 DJB 大鼠中 miR-200a 的整体下调表明胰岛素敏感性受损，而糖尿病大鼠中 miR-200a 的上调表明糖尿病得到改善。确定了一种新机制，其中 miR-200a 调节 Rheb 介导的 DJB 胰岛素抵抗改善。研究结果表明，应该进一步探索 miR-200a 作为治疗糖尿病的潜在靶点。
Duodenal–jejunal bypass (DJB) surgery can induce the rapid and durable remission of diabetes. Recent studies indicate that ameliorated hepatic insulin resistance and improved insulin signaling might contribute to the diabetic control observed after DJB. Ras homolog enriched in brain (Rheb) is reported to have an important role in insulin pathway, and some microRNAs (miRNAs) have been found to regulate Rheb. This study was conducted to investigate the effects of DJB on hepatic insulin resistance and the effects of miRNA-200a, a Rheb-targeting miRNA, on the development of DJB-induced amelioration in hepatic insulin resistance. We investigated hepatic insulin signaling change and mapped the hepatic miRNAome involved in a rat model of DJB. We studied the effects of miR-200a on Rheb signaling pathway in buffalo rat liver cell lines. Liver tissues were studied and glucose tolerance tests were conducted in DJB rats injected with lentivirus encoding miR-200a inhibitor and diabetic rats injected with miR-200a mimic. Rheb is a potential target of miR-200a. Transfection with an miR-200a inhibitor increased Rheb protein levels and enhanced the feedback action on insulin receptor substrate-dependent insulin signaling, whereas transfection with an miR-200a mimic produced the opposite effects. A luciferase assay confirmed that miR-200a bind to the 3′UTR (untranslated regions) of Rheb. Global downregulation of miR-200a in DJB rats showed impaired insulin sensitivity whereas upregulation of miR-200a in diabetic rats showed amelioration of diabetes. A novel mechanism was identified, in which miR-200a regulates the Rheb-mediated amelioration of insulin resistance in DJB. The findings suggest miR-200a should be further explored as a potential target for the treatment of diabetes.