糖脂代谢紊乱是2型糖尿病微血管并发症的基础病变，致死率高，亟待开发兼有降糖调脂作用的药物。近年发现前蛋白转化酶枯草溶菌素9（PCSK9）与糖脂代谢存在极大关联，我们前期发现：虎杖苷可结合于PCSK9晶体活性口袋，且糖尿病模型动物肝脏糖脂代谢异常的同时，伴随SREBP-1c核蛋白水平和PCSK9表达的增加，而虎杖苷可有效逆转该现象。进一步研究发现：胰岛素抵抗HepG2细胞中，SREBP-1c核转位增多，伴随PCSK9表达的增加，虎杖苷抑制二者表达的同时还可减少PCSK9-LDLR的结合。由此我们提出假说：虎杖苷除直接结合PCSK9外，还可通过抑制SREBP-1c-PCSK9启动子活性来减少PCSK9转录翻译，协同发挥降糖调脂作用。本项目拟采用体内外模型，筛选出虎杖苷糖脂代谢调节的关键蛋白，并探寻PCSK9介导虎杖苷糖脂代谢调节相关通路，为将虎杖苷开发为具有特定靶点的新型降糖调脂药物提供依据。

The disorder of glucose and lipid metabolism is the basis of microvascular complications in type 2 diabetes mellitus, which has high mortality and sounds the alarm to develop drugs with both hypoglycemic and lipid regulation effects. Nowadays researchers have found that proprotein convertase subtilisin/kexin type 9 (PCSK9) is highly correlated with glucose and lipid metabolism. In our previous study, we found that Polydatin could bind to the active pocket of PCSK9 crystal structure, besides, abnormal glucose and lipid metabolism in the liver of diabetic model animals was accompanied by increased SREBP-1c nucleoprotein level and PCSK9 expression, which could be reversed by Polydatin primely. Further research found that the nucleus translocation of SREBP-1c improved, with the increase of PCSK9 expression in insulin resistant HepG2 cells, and Polydatin can not only inhibit their expression but also reduce the combination of PCSK9-LDLR.Thus we propose a hypothesis: in addition to directly binding to PCSK9, Polydatin can also reduce PCSK9 transcription and translation by inhibiting the activity of SREBP-1c-PCSK9 promoter, thus synergistically exerting the hypoglycemic and lipid-regulating effects. This project intends to use the vitro and vivo models, screening the key protein of glucolipid metabolism, and explore PCSK9 correlated signaling pathway in glucolipid metabolic regulation under the condition of Polydatin treatment, which will provide a scientific basis for developing Polydatin as a new drug with a specific target in hypoglycemic and lipid regulation.