胆固醇逆转运（RCT）是机体排出多余胆固醇的基本途径，实现下调LDL-C水平、同时提高HDL-C介导的胆固醇流出与代谢功能，有望从根本上调节血脂平衡，预防动脉粥样硬化斑块形成。依据同时激活PPARγ和LXRα，比激活单靶点更能加快胆固醇流出的脂代谢新进展，本项目提出PPARγ/LXRα双靶点药物的研究思路，基于RCT途径，通过PPARγ-LXRα-ABC信号通路协同作用，加速胆固醇流出与下游代谢，提高RCT功能。课题组前期合成的刺芒柄花素十一烯醚有较好的调血脂活性，对PPARγ和LXRα均有激活作用，在此基础上，针对双靶点，运用“骨架跃迁”的方法构建稠杂环或甾环等亲脂性母核，在连接链或亲水性末端引入能提高双靶点选择性的药效团，设计合成高亲和性双靶点分子，从细胞、动物和分子水平评价生物活性，获得调血脂活性和类药性好、副作用小的先导化合物，并探索通过RCT途径调节血脂、减少肝脂沉积的作用机制。

Reverse cholesterol transport (RCT) is the main and basic pathway by which excess cholesterol is transported from the macrophages back to the liver for clearance. The reduction of LDL-C level and the function improvement of HDL-C mediated cholesterol efflux and metabolism are expected to prevent lipidosis and atherosclerotic plaque formation, and fundamentally treat the dyslipidemia. According to the latest research advances in lipid homeostasis, co-activation of PPARγ and LXRα should accelerate cholesterol efflux more effectively than either one individually. Herein we innovatively suggest that PPARγ/LXRα dual agonist may be able to accelerate cholesterol efflux from macrophages, which is the rate-determining step of RCT, and enhance the RCT function synergistically via PPARγ-LXRα-ABC pathway. Previous studies from our group found that formononetin undecylenic ether synthesized in our laboratory upregulated PPARγ and LXRα in pre-adipocytes and exhibited obvious effects of lowering total cholesterol. In this research project, novel compounds will be creatively designed by using formononetin undecylenic ether as lead compound and PPARγ/LXRα as dual targets. New lipophilic fused-heterocycle or steroidal skeleton will be built to substitute for formononetin through “scaffold hopping” strategy. Under the guide of diversity-oriented synthesis, active functional groups which help to improve the affinity and selectivity of receptors will be introduced to the linkage part and the hydrophilic end of the target molecules in order to get drug-like compounds with PPARγ/LXRα dual agonism. Their bioactivities of accelerating cholesterol efflux and regulating lipid homeostasis will be evaluated in vitro and vivo. The molecular mechanism of promoting RCT and decreasing hepatic lipidosis via PPARγ/LXRα signaling pathway will also be explored.