二甲双胍降低大鼠肝脏胆固醇和甘油三酯含量的机制探讨  

Mechanism of metformin decreasing the cholesterol and triglyceride contents in the liver of high-fat diet fed rats

作　　者：王斐[1] 刘毅[1] 高冠起[3] 郭华[2] 崔彬[2] 高聆[2] 赵家军[1] 

机构地区：[1]山东大学临床医学院省立医院内分泌科,济南250021 [2]山东大学临床医学院省立医院中心实验室,济南250021 [3]临沂市人民医院内分泌科

出　　处：《中华内分泌代谢杂志》2008年第2期204-207,共4页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金资助项目（30670994）;山东省自然科学基金资助项目（Y2005C03）;山东省卫生厅项目（2005HZ061）

摘　　要：目的观察二甲双胍对长期高饱和脂肪酸饲养大鼠肝脏腺苷酸活化蛋白激酶α（AMPKα）和PPARα表达和活性的影响，探讨二甲双胍降低肝脏胆固醇（TC）和甘油三酯（TG）含量的可能机制。方法Wistar雄性大鼠30只，随机等分为：对照组（C组）、高脂组（HF组）和高脂加二甲双胍组（Met组，高脂喂养4个月，第5个月加用二甲双胍灌胃1个月），喂养共5个月，测定血清、肝脏组织中的TC和TG含量；分别应用实时PCR、Western印迹检测肝脏AMPKα和PPARα的基因转录、蛋白表达和活性水平；PPARα转录因子DNA结合活性测定用ELISA法。结果与C组比较，HF组大鼠肝脏AMPKα2和PPARα mRNA表达水平显著降低（均P〈0．05）；AMPKα蛋白表达及活性显著降低（均P〈0．05），PPARα蛋白表达及DNA结合活性分别降低48．6％、21．6％（均P〉0．05）；肝脏TC、TG含量（均P〈0．05）和血TC、TG水平（均P〈0．01）均显著增高。与HF组比较，Met组肝脏AMPKα2 mRNA和蛋白表达及活性显著增高（均P〈0．05），PPARα蛋白表达增高56．5％（P〉0．05），其DNA结合活性显著增高（P〈0．05）；肝脏TC、TG含量和血TC、TG水平均显著降低（均P〈0．05）。结论二甲双胍降低长期高脂饲养所致的大鼠肝脏、血中TC、TG水平的增高，可能与其激活肝细胞AMPKα及PPARα有关。Objective To detect the expression and activity of AMP-activated protein kinase α subunit （AMPKα） and peroxisome proliferator-activated receptor-α （PPARα） in liver of high-fat fed rats treated with mefformin, and to investigate the mechanisms underlying mefformin decreasing the total cholesterol （TC） and triglyceride （TG） contents of the liver. Methods Total 30 male Wistar rats were randomly divided into control group （ group C）, high-fat diet fed group （ group HF） and high-fat diet feeding plus mefformin treatment group （group Met,mefformin was administered orally at the last month of high-fat diet feeding）. After feeding for 5 months, TC and TG in liver and sera were determined, respectively. The mRNA and protein levels and activity of AMPKα and PPARα in the liver were determined by real-time PCR and Western blotting. The activity of PPARα transcriptor binding to DNA was detected by ELISA. Results Five months of high-fat diet feeding induced a significant decrease in AMPKα and phosphorylated-AMPKα protein expression as well as AMPKα2 and PPARα mRNA levels in the liver of rats （ all P 〈 0.05 ） , while it did not alter PPARα protein expresssion and the PPARα activity binding to DNA as well as AMPKαl mRNA levels. The TC and TG contents in the liver （P 〈0.05 ） and serum （P 〈 0.05 ） were sharply increased in group HF than those in group C. Treatment with mefformin for 1 month led to a marked increase of AMPKα2 mRNA level, AMPKα and phosphorylated-AMPKα protein expression as well as the PPARα activity in group Met compared with group HF（ all P 〈 0.05 ）, while the PPARα protein expression and the PPARα mRNA level did not show significant change. Consistent with these findings, the TC and TG contents in rat liver as well as sera were strikingly decreased （ all P 〈 0.05 ）. Conclusion The activations of AMPKα and PPARα induced by mefformin may contribute to the decrease of TC and TG content in liver and sera of the high-fat fed rats.

关 键 词：二甲双胍 高脂饲养 腺苷酸活化蛋白激酶 PPARΑ 肝 大鼠 WISTAR 

分 类 号：R96[医药卫生—药理学]