MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids
MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids
复制标题
MicroRNA-26a 调节胰岛素敏感性以及葡萄糖和脂质的代谢。
DOI：
10.1172/jci75438
复制
发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Huang, Wendong
中科院分区：
文献类型：
--
作者：
Fu, Xianghui;Dong, Bingning;Huang, Wendong
2型糖尿病（T2 D）的特征是胰岛素抵抗和肝葡萄糖产生增加，但这些异常的分子机制知之甚少。microRNA（miRs）是一类小的非编码RNA，其与人类疾病（包括T2 D）的调节有关。miR-26 a在肿瘤发生中起着重要作用，但其在细胞代谢中的作用尚不清楚。在这里，我们确定miR-26 a调节胰岛素信号传导和葡萄糖和脂质代谢。与瘦人相比，超重的人肝脏中miR-26 a的表达减少。此外，与对照动物相比，miR-26在2个肥胖小鼠模型中下调。在高脂饮食喂养的小鼠中，miR-26 a的整体或肝脏特异性过表达改善了胰岛素敏感性，减少了肝脏葡萄糖的产生，并减少了脂肪酸的合成，从而预防了肥胖诱导的代谢并发症。相反，在常规饮食喂养的小鼠中内源性miR-26 a的沉默损害胰岛素敏感性，增加葡萄糖产生，并增加脂肪酸合成。miR-26 a靶向肝脏代谢和胰岛素信号传导的几个关键调节因子。这些发现揭示了miR-26 a作为肝脏代谢的调节剂，并建议miR-26 a应进一步探索作为T2 D治疗的潜在靶点。
Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenes-is; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.