姜黄素在SREBP-2调控NPC1L1对小肠胆固醇的吸收及预防胆囊胆固醇性结石形成中作用的研究

Nowadays, intestinal cholesterol absorption in the molecular mechanism of gallstone formation is a hot issue in the research of cholelithiasis. Studying the regulation factor of intestinal cholesterol absorption has a great significance for the prevention and treatment of cholesterol gallstone. NPC1L1 is the cholesterol transporter in intestinal epithelium, which is regulated by SREBP-2. Curcumin can down-regulate the expression of SREBP-2 and inhibit the NPC1L1 activity, then decrease the absorption of intestinal cholesterol. In preliminary study, we found EZET can prevent the formation of cholesterol gallstone. Based on this founding, we study the affection of curcumin to intestinal cholesterol absorption on transgenic and gene knockout animal models by optical in vivo imaging, Rt-PCR and gel shift assay. By exploring SREBP-2 mediates the modulation of intestinal NPC1L1 expression by curcumin, we want to clarify the mechanism of curcumin decreasing blood cholesterol and preventing the formation of gallstone, which can provide reliable experimental evidence for cholesterol gallstone clinic early prevention and drug treatment.

小肠胆固醇吸收在胆囊结石形成中作用的分子学机制的研究，是国内外胆石成因研究领域的热点问题。前期研究证实，NPC1L1是小肠粘膜重要的胆固醇转运载体，抑制其功能，可以降低小肠胆固醇吸收，对胆囊胆固醇结石的预防和治疗具有重要意义。SREBP-2是调控NPC1L1表达的重要因子，姜黄素可以下调SREBP-2的表达，间接抑制NPC1L1的活性，降低小肠胆固醇吸收。本项目旨在通过前期依折麦布预防饮食诱导的胆囊结石形成作用的研究基础上，通过转基因和基因敲除动物模型的建立，应用活体动物体内光学成像、Rt-PCR、电泳迁移率测定等技术，研究活体动物体内姜黄素对小肠胆固醇吸收的影响，探讨姜黄素干预下小肠上皮SREBP-2表达水平和NPC1L1活性变化，阐明姜黄素降低血清胆固醇及预防胆囊结石形成的分子学机制，为胆囊胆固醇结石病的早期预防和药物治疗提供可靠的实验依据。

胆囊结石是由于胆囊胆汁生化学状态失衡引发的临床疾病，既往研究表明，肠腔中饮食来源和胆汁来源的胆固醇的获得和小肠胆固醇吸收的效能与结石易感群体的成石状态密切相关。姜黄素在心血管疾病领域常用于降低血脂。然而，姜黄素是否能够通过改变胆固醇代谢，进而影响高脂饮食小鼠胆囊结石的形成尚未有研究。本课题通过构建高脂饮食小鼠模型，联合姜黄素和/或胡椒碱，观察小鼠胆囊成石情况及相关指标，检测小鼠小肠粘膜NPC1L1及SREBP2 mRNA和蛋白表达，结果提示姜黄素能够预防胆囊结石的形成，NPC1L1 和 SREBP2 可能参与了这个过程，胡椒碱作为生物利用度增强剂，能够增加姜黄素的生物利用度，增强姜黄素预防胆囊结石形成的作用。本研究可能为通过日常饮食预防胆囊结石提供新的思路。