姜辣素影响胆固醇代谢的分子机制研究

Ginger (Zingiber officinale Roscoe) is both a medicinal plant and a traditional food that has been widely used in China. Gingerols, the active ingredient of ginger mainly contained 3 kinds of gingerols and 3 kinds of shogaols. Our preliminary data have showed that gingerols can regulate plasma cholesterol level, but which ones have cholesterol-lowering effect and how to regulate cholesterol metabolism are still unknown. In this study, we will investigate the mechanism of cholesterol-lowering effect of gingerols in vitro and in vivo. First, we will use human liver cell and Caco2 cell to be the liver cholesterol pool and intestine cholesterol absorption models, to screen the key cholesterol-lowering components of gingerols (GS1, GS2). Then we use hamster as an animal model, to study the effect of gingerols on the five major cholesterol metabolism pathways,which including cholesterol de novo synthesis, cholesterol absorption, liver cholesterol efflux, reverse cholesterol transport and cholesterol excretion , as well as their involved gene and protein expression. Then we will combine the molecular data and biochemical index of blood, organ, feces etc, to comprehensively and systematically investigate the mechanism of regulation of cholesterol metabolism by gingerols.

生姜是我国传统的药食兼用资源，其活性成分姜辣素主要包括3种姜酚和3种姜烯酚。我们的前期研究发现姜辣素提取物具有调节血浆胆固醇的作用，但其发挥作用的关键成分和作用机制不十分清楚。本课题拟从细胞-动物两个层面研究姜辣素调节胆固醇代谢的作用机制。首先利用人肝细胞和肠细胞模拟人体肝脏胆固醇代谢及小肠胆固醇吸收模型，筛选出姜辣素调节胆固醇的关键成分（最强GS1，次强GS2）；然后再利用与人类胆固醇代谢相近的仓鼠作为动物模型，通过喂养正常饲料、对照饲料（含0.1%高胆固醇）、对照饲料+0.5%姜辣素提取物、对照饲料+0.5%GS1、对照饲料+0.5%GS2，从胆固醇代谢的5大通路，即胆固醇合成、胆固醇吸收、肝脏胆固醇排出、胆固醇逆转路回肝脏重新代谢和胆固醇排泄中所涉及的主要基因的mRNA和蛋白入手，并结合动物血液、器官及粪便等生化指标，全面探讨姜辣素影响胆固醇代谢的分子作用机制。

姜辣素是生姜的辣味成分，是由姜酚和姜烯酚组成的混合物，是生姜中重要的活性物质。本课题从动物-细胞两个层面研究姜辣素调节胆固醇代谢的作用机制。首先利用仓鼠作为动物模型，分为三组，对照组、添加0.5%和1%的姜辣素组。实验结果表明姜辣素可有效降低血胆固醇、肝脏胆固醇及动脉粥样硬化斑块，并且增加粪便中性固醇和酸性固醇排泄，呈现剂量效应。初步结论姜辣素可通过以下三个途径起到降胆固醇的作用：①阻碍小肠对胆固醇的吸收;②促进肝脏胆固醇转化为胆汁酸;③促进胆固醇及胆汁酸的排泄。其次利用HepG2作为细胞模型，比较姜辣素中主要成分6-姜酚、8-姜酚和10-姜酚的胆固醇调节效能，结果表明，6-姜酚、8-姜酚和10-姜酚均有效降低细胞胆固醇量，其中10-姜酚降胆固醇效果最佳。本课题组进一步以6-姜酚为代表探讨姜辣素调节胆固醇代谢的分子作用机制，通过结合LDL-uptake实验、Real time PCR和Western blot数据，发现6-姜酚降低HepG2细胞总胆固醇和游离胆固醇的主要机制是通过①上调控制胆固醇“入”的SREBP-2及其靶基因LDLR，增加了肝细胞对LDL的摄取；②上调控制胆固醇“出”的LXRα及其靶基因ABCA1，促进了胆固醇排出肝细胞。因此，6-姜酚加速了胆固醇在肝细胞的代谢过程，从而起到积极调节血胆固醇的作用，该研究为姜辣素在调节血胆固醇方面的研究提供了重要的科学依据。