新型ABCA1上调剂E17241改善糖脂代谢紊乱的机制研究

ATP-binding cassette transporter protein A1 (ABCA1) plays important roles in regulating glucose homeostasis, lipid metabolism, cholesterol homeotasis and improving insulin function. Regulating ABCA1 expression could reduce the occurrence of T2D. Targeting regulation of ABCA1 expression could also have protection of cardiovascular disease through reverse cholesterol transport. Our previous results have proved that E17241 is a potent ABCA1 up-regulator, which could significantly increase the expression of ABCA1 in vitro. E17241 could also significantly reduce sizes and numbers of the plaques, lower the fasting plasma glucose level and increase liver ABCA1 expression in atherosclerosis model mice. Compared with the thiazolidinediones, E17241 had a selective regulation on fatty acid metabolism related genes. These results indicated that E17241 had a potential role in regulating glucose and lipid metabolism. In this study, we intend to use E17241 as a small molecule probe to convince its effect on regulating glucose and lipid homeostasis and exclusive the corresponding mechanism and network in vitro and in vivo. Through these experiments, we thus hope to convince the possibility of ABCA1 as a T2D treating target and the feasibility of E17241 as a new T2D therapeutic agent, and ultimately provide a new target and a leading compound for treating T2D.

ATP结合盒转运体蛋白A1（ABCA1）在机体调节葡萄糖、脂肪酸以及胆固醇代谢平衡、改善胰岛功能中具有重要的作用。调节ABCA1的表达被认为能减少2型糖尿病（T2D）的发生，同时通过促进胆固醇逆转运发挥心血管保护作用。我们前期发现并证明化合物E17241为ABCA1表达上调剂，其在体内外能显著增加ABCA1的表达、显著减少动脉粥样硬化模型小鼠中斑块的面积和数量、降低血糖、且对脂肪酸代谢相关基因具有一定的选择性（与噻唑烷二酮相比），说明E17241具有很好的调节糖脂代谢紊乱的潜力。我们拟以小分子化合物E17241为探针，利用糖尿病模型小鼠以及体外细胞实验证明ABCA1上调剂E17241对糖脂代谢紊乱的调节作用，阐明E17241及ABCA1对糖脂代谢的调节机制及网络，以便证明ABCA1作为T2D治疗靶标和E17241作为新型T2D治疗剂的可行性，最终为T2D药物的发现提供新靶标和先导物。

ATP结合盒转运体蛋白A1（ABCA1）在机体调节葡萄糖、脂肪酸以及胆固醇代谢平衡、改善胰岛功能中具有重要的作用。调节ABCA1的表达被认为能减少2型糖尿病（T2D）的发生，同时通过促进胆固醇逆转运发挥心血管保护作用。我们发现并证明化合物E17241为ABCA1表达上调剂，其在体内外能显著增加ABCA1的mRN及蛋白表达、显著减少高脂饮食诱导的ApoE-/-动脉粥样硬化模型小鼠中主动脉全长及心脏流出道中斑块的面积和数量、显著降低血清中TC、血糖水平、减少肝脏中TC含量，增加粪便胆固醇含量；E17241能在T2D 模型KKAy小鼠中降低血糖，改善葡萄糖耐受和胰岛素抵抗，且对脂肪酸代谢相关基因具有一定的选择性（与噻唑烷二酮相比）；我们的结果说明E17241在动物体内具有很好的调节糖脂代谢紊乱的潜力。此外，我们通过对生物素对E17241进行标记，利用蛋白芯片及CO-IP等手段，发现E17241通过激活PKCζ-NR途径上调ABCA1的表达；并且在ApoE-/-动脉粥样硬化模型小鼠以及KKAy小鼠中，E17241给药能增加PKCζ的磷酸化，从而影响糖脂代谢。总之，我们利用动脉粥样硬化及糖尿病模型小鼠首次证明ABCA1上调剂E17241具有对糖脂代谢紊乱的调节作用，阐明E17241通过PKCζ-ABCA1通路发挥对糖脂代谢的调节机制。为ABCA1作为T2D治疗靶标和E17241作为新型T2D治疗剂的可行性提供依据。在本课题的资助下，共发表论文9篇，包括SCI 论文7 篇，核心期刊2篇；授权专利1 1项，申请2项。