Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling
Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling
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肝脏 miR-378 靶向 p110α，并通过调节肝脏胰岛素信号传导来控制葡萄糖和脂质稳态。
DOI：
10.1038/ncomms6684
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发表时间：
2014-12-01
影响因子：
16.6
通讯作者：
Ying, Hao
中科院分区：
文献类型：
--
作者：
Liu, Wei;Cao, Hongchao;Ying, Hao
了解组织中胰岛素信号的调节提供了对生理学和疾病中碳水化合物和脂质代谢的见解。在这里，我们发现肝脏miR-378/378* 表达在小鼠禁食和再喂养时发生变化。过表达肝脏miR-378/378* 的小鼠表现出纯肝脏胰岛素抵抗。miR-378通过靶向p110 α抑制肝脏胰岛素信号传导，p110 α是PI 3 K的亚基，因此是胰岛素信号传导的关键组分。肝脏p110 α的敲低模拟miR-378的作用，而p110 α表达的恢复消除了miR-378对胰岛素信号传导的作用及其对葡萄糖和脂质稳态的全身作用。miR-378/378* 敲除小鼠显示出低血糖和肝脏甘油三酯水平升高，胰岛素敏感性增强。在miR-378/378* 敲除小鼠中抑制肝脏p110 α可纠正异常葡萄糖耐量。最后，我们发现肝脏miR-378/378* 的过表达可以改善ob/ob小鼠的肝脏脂肪变性，而不会加重高血糖。我们的研究结果确立了空腹反应性miR-378作为肝脏胰岛素信号传导的关键调节因子。
Understanding the regulation of insulin signalling in tissues provides insights into carbohydrate and lipid metabolism in physiology and disease. Here we show that hepatic miR-378/378* expression changes in response to fasting and refeeding in mice. Mice overexpressing hepatic miR-378/378* exhibit pure hepatic insulin resistance. miR-378 inhibits hepatic insulin signalling through targeting p110 alpha, a subunit of PI3K and hence a critical component of insulin signalling. Knockdown of hepatic p110 alpha mimics the effect of miR-378, while restoration of p110 alpha expression abolishes the action of miR-378 on insulin signalling as well as its systemic effects on glucose and lipid homeostasis. miR-378/378* knockout mice display hypoglycemia and increased hepatic triglyceride level with enhanced insulin sensitivity. Inhibition of hepatic p110 alpha in miR-378/378* knockout mice corrects the abnormal glucose tolerance. Finally, we show that overexpression of hepatic miR-378/378* ameliorates hepatic steatosis in ob/ob mice without exacerbating hyperglycemia. Our findings establish fasting-responsive miR-378 as a critical regulator of hepatic insulin signalling.