人参皂苷Re改善脂代谢的机制及其作用靶点研究

Dyslipidaemia (high levels of low-density lipoprotein cholesterol [LDL-C] and triglycerides, and low levels of high-density lipoprotein cholesterol [HDL-C]) is one of the major established risk factors for the occurrence and development of atherosclerosis. This calls for more safe and effective additional treatment options. We previously found that Ginsenoside Re(Re), a compound derived from Panax ginseng, can significantly improve insulin sensitivity in high-fat diet induced obese (DIO) rats. It can also have a strong effect in improving lipid metabolism by lowering cholesterol and triglyceride. However, the molecular basis of its action remains unknown. Here we design to examine anti-dyslipidemic activities of Re in DIO rats and genetic obese db/db mice to confirm its improvement on lipid metabolism. We would like to apply radioisotopic tracers to study the effect of Re on synthesis and decomposition of cholesterol and triglyceride in vitro. Lots of modern molecular biology methods such as Real-time PCR, Western blot, siRNA interference, surface plasmon resonance technology (SPR）and competitive binding assay will be used to dissect the molecular mechanisms and find out the target of Re. Our original work will be strategically important for research and manufacturing of self-developed traditional Chinese medicine for regulation of lipid metabolism.

血脂异常是冠心病、脑卒中等心脑血管疾病的重要危险因素，已成为严重危害人类健康的公共卫生问题。为降低发生心脑血管病的风险、减少目前调脂药物治疗的不良反应，亟需开发安全有效的新型调脂药物。本课题组前期研究发现：人参皂苷Re可明显改善高脂饮食诱导肥胖大鼠的胰岛素抵抗，显著降低其血浆胆固醇（Cho）和甘油三酯（TG）水平。在本课题中，我们拟应用db/db小鼠和高脂饮食喂养诱导肥胖大鼠，从整体评价Re对脂代谢的影响，并将利用同位素示踪技术精确研究Re对Cho和TG合成和分谢过程的作用，在此基础上结合Real-time PCR、Western blot、siRNA干扰等现代分子生物研究方法，阐明人参皂苷Re作用机制及靶点。这对于开发和应用具有自主知识产权的中药调节脂代谢的新药，具有十分重要的意义。

前期研究证实人参皂苷Re干预可使高脂饮食诱导肥胖大鼠胰岛素抵抗明显改善, 显著降低其血浆胆固醇（Cho）和甘油三酯（TG）水平；本课题中,基于人参皂苷Re治疗高脂饮食诱导肥胖（DIO）大鼠的工作基础上，我们应用有遗传缺陷的肥胖db/db小鼠为模型，深入探讨了人参皂苷Re对不同肥胖动物模型脂代谢紊乱的改善作用及机制。结果发现人参皂苷Re亦可明显降低肥胖小鼠的体重，改善db/db小鼠的脂代谢，显著降低其血清甘油三酯和总胆固醇水平，经人参皂苷Re处理后肝脏组织中的甘油三酯沉积也明显减少；通过实时荧光定量PCR检测发现：肝脏组织中与脂肪酸β氧化相关基因如：PPARα、LCAD、MCAD等的mRNA水平显著升高，另外在脂肪组织中与上述脂肪酸β氧化相关基因的mRNA水平亦显著升高；以上结果提示人参皂苷Re通过激活肝脏、脂肪组织AMPK 、 PPARα等信号通路，调控并改善机体的脂代谢；我们的研究结果对于开发和应用具有自主知识产权的调节脂代谢的新型中药具有十分重要的意义。