甘油一酯转酰基酶药物治疗肥胖的新靶点

Role of monoacylglycerol acyltransferase in obesity

目的探讨肥胖产生的机制 ,寻找致病因素 ,以此作为肥胖治疗的新靶点和开发新药。方法使用肥胖模型动物OLETF大鼠 ,在纠正动物过食行为后 ,考察体质量、体脂肪、内脏脂肪和血浆中甘油三酯含量的变化。测定肝素注射后血浆中的LPL和脂肪合成关键酶MGAT和DGAT的活性。结果动物限食后 ,肥胖症状得到明显改善 ,但是与正常动物相比 ,虽然体质量没有显著差异 ,但体脂肪、内脏脂肪和血浆甘油三酯含量仍显著升高。酶活性测定的结果表明 ,OLETF动物小肠MGAT活性显著高于对照组。结论MGAT活性异常升高是引起OLETF动物肥胖的原因之一 ,MGAT可能成为治疗肥胖的新靶点。阻断MGAT活性的化合物可能开发为治疗肥胖的新型药物。

Objective To elucidate the mechanism of obesity,identify the causative factor(s),and consequently find potential therapeutic intervention point(s) on obesity and develop new drugs.Methods An obesity model animal OLETF rat was used in this study.After the hyperphagia behavior of a rat was corrected,the preventive effects on the development of obesity were investigated.Changes in body weight,body fat,introabdominal fat weight and plasma triglyceride (TG) were measured.Activities of the key enzymes,including lipoprotein lipase (LPL),monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) were assayed.Results After calorie restriction,the body weight in food-restricted OLETF rats were almost the same as that of the control group,but the body fat,introabdominal fat weight and plasma TG were significantly higher in restricted OLETF than the value in the control group. The activity assay of enzyme showed that MGAT activity in the small intestines from both satiated and restricted OLETF rats was significantly increased compared with the control group,Activities of DGAT showed no significant difference among the three groups.LPL in satiated OLETF rats was significantly decreased,but normal in the restricted OLETF.Conclusion The increased activity of MGAT is a causative factor which leads to obesity in OLETF rats,and may become a potential therapeutic intervention point,MGAT inhibitor is hopeful of being developed into a new drug for obesity.