let-7/SERCA2b信号通路在肥胖诱导胰岛素抵抗中的作用

肥胖成为公众关注的健康焦点问题，与肥胖相关的胰岛素抵抗是引起非酒精性脂肪性肝病的重要原因。内质网上的钙离子ATPase（SERCA）负责维持内质网高浓度的钙离子，保证内质网的正常功能。抑制SERCA活性会诱发内质网应激。我们近期研究发现，高脂饮食喂食大鼠肝脏的SERCA2b蛋白水平显著下调，而mRNA水平未变。因此，我们猜测microRNAs可能参与了SERCA2b的调控。利用microarray对大鼠肝脏的miRNA表达谱，我们发现一个高度保守的miRNA rno-let-7在肥胖大鼠肝脏内的表达上调。本项目探讨在高脂饮食喂食的肥胖大鼠中，是否上调的rno-let-7抑制SERCA2b蛋白水平，导致肝细胞出现内质网应激，进而产生肝脏胰岛素抵抗。我们还将研究肥胖上调rno-let-7的信号通路。本研究将揭示一个新的肥胖所致胰岛素抵抗的途径。

Obesity is one of the greatest public health concerns. Obesity-associated insulin resistance is regarded as an important factor that contributes to the development of nonalcoholic fatty liver disease. A high level of Ca2+ in the endoplasmic reticulum (ER), which is maintained by sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), is forcible for normal ER function. The inhibition of SERCA will trigger ER stress. In our recent study, our results indicated that SERCA2b protein levels, rather than mRNA levels, were dramatically down-regulated in the liver of rats fed a high-fat diet (HFD), implicating that microRNAs may regulate SERCA2b. Using miRNA microarray analysis, we found that a conserved mRNA, rno-let-7, was remarkably up-regulated in the liver of obese rats. In the current study, we will test whether the increase in rno-let-7 inhibit the SERCA2b protein in obese rats, which leads to insulin resistance by ER stress. Furthermore, we will investigate which the signaling pathways are involved in up-regulation of rno-let-7 in the liver of obese rats. Our study will reveal a novel mechanism underlying obesity-induced insulin resistance.