miR-30c－胰岛素信号通路在肝脏脂质合成和糖代谢中的作用和调控机制

他汀降脂增加新发糖尿病的风险促使人们寻找兼顾糖脂代谢动态平衡的降脂治疗新靶点。最新研究发现，miR-30c通过减少肝脏脂质合成和脂蛋白分泌，降低血脂、减轻动脉粥样硬化病变程度，但其减少肝脏脂质合成的具体机制不明，对糖代谢的影响未知。本课题组前期研究发现，miR-30c可抑制肝细胞胰岛素敏感性，生物信息学预测miR-30c具有7个胰岛素信号通路相关靶点。据此提出miR-30c通过调控肝脏胰岛素信号通路活性减少肝脏脂质合成，并同时影响肝脏糖代谢。在此基础上，本项目将进一步采用基因芯片、信号通路磷酸化芯片、生物信息学分析和基因操作等分子生物学技术确认miR-30c的靶基因、与肝脏胰岛素信号通路及脂质合成、糖异生、糖原合成的关系，并结合小鼠体内实验阐明miR-30c－胰岛素信号通路在肝脏脂质合成和糖代谢中的调控机制。本项目的完成，将为探索miRNAs应用于临床高脂血症的治疗提供新的理论和实验依据。

The increased risk of new diabetes with statins necessitates new lipid lowering strategies, which balance the lipid and glucose metabolism. Recent evidence proves that miR-30c curtails hyperlipidemia and atherosclerosis by decreasing hepatic lipid biosynthesis and lipoprotein secretion, however, the mechanisms underlying the reduced lipogenesis remains unclear, and little is known about the regulation of miR-30c on the hepatic glucose metabolism. Our preliminary study showed that miR-30c inhibited the insulin sensitivity in HepG2 cells, and bioinformatics analysis based on seed recognition identified 7 possible target genes of miR-30c involved in insulin signaling pathway. On this basis, with cDNA microarray, signaling pathway phospho antibody array and cell function experiments, this project will further identify the target genes and determine the function and regulatory mechanism of miR-30c in gluconeogenesis, glycogen synthesis and lipogenesis; wild-type and in vivo experiments with mouse are used to clarify the role of miR-30c and insulin signaling in the hepatic lipogenesis and glucose metabolism. Completion of this project will contribute to open new perspectives to improve the research development and clinical management of hyperlipidemia.