LXRβ选择性激动剂抗动脉粥样硬化的药理学及其作用机制研究

Liver X receptor (LXR), a member of the nuclear receptor family, has become a new target of anti-atherosclerosis. LXR plays an important role in various aspects of cholesterol metabolism, including reverse cholesterol transport process, promoting bile cholesterol secretion, inhibiting the intestinal absorption of cholesterol, and maintaining intracellular cholesterol homeostasis of the body. Meanwhile, LXR is also involved in the regulation of inflammation response pathway in macrophages. However, LXR agonists existing were found to have side effects in lipid accumulation and increased triglyceride levels in the blood. LXRα is regarded as the main subtype for regulating the lipogenesis relating genes expression. In contrast, activation of LXRβ does not lead to this situation. Therefore, the development of novel selective LXRβ agonists which have good activity and fewer side effects are crucial for the treatment of atherosclerosis. Based on our previous work, IMB-808 was identified by screening with selective agonist activity of LXRβ and fewer side effects. In this research, we will explore the pharmacological effects of anti-atherosclerosis in vitro and in vivo. Furthermore, the anti-atherosclerosis mechanism of IMB-808 which is cross-regulated cholesterol metabolism and inflammation response mediated by LXRβ will be clarified. In general, our project will provide a solid basis for anti-atherosclerosis drug development in the future.

核受体LXR直接调控参与胆固醇代谢途径中诸多关键靶基因的表达，对于维持机体内胆固醇水平至关重要，同时与巨噬细胞中的炎症反应调控紧密相关，是抗动脉粥样硬化的重要靶标。然而，目前已有的LXR激动剂会造成肝脏中的脂肪堆积、血液中甘油三酯升高等副作用。研究表明，LXRα是主要调控肝内脂肪生成相关基因表达的亚型，而LXRβ在被激动剂激活时，并不会引起类似的副作用。因此，获得具有活性好、副作用小的新型LXRβ选择性激动剂，将有利于发现更加安全有效的治疗动脉粥样硬化药物。本项目基于前期通过筛选获得的小分子化合物IMB-808，部分体外结果证明该化合物具有很好的LXRβ选择性激动剂活性，且毒副作用较小。通过对其在体外、体内水平的抗动脉粥样硬化作用进行深入的药理学研究，探讨该化合物通过LXRβ交叉调控胆固醇代谢及炎症反应介导抗动脉粥样硬化的作用机制。这将为后期抗动脉粥样硬化药物的开发奠定基础。