短期奥氮平给药改变大鼠肝脏脂代谢:量效关系研究

Short-Term Administration of Olanzapine Altered Lipid Metabolism in Rat Liver——A Study of Dose-Response Relationship

临床一线精神病治疗药物奥氮平(Olanzapine,Ola)引发糖脂代谢异常,风险极大,但作用机制仍不明确.模拟临床给药方式,比较不同剂量Ola短期作用后介导机体脂代谢异常的差异,并探讨其可能的机制.设置0.25,0.5,1.0和2.0 mg/kg Ola 4个剂量组,连续处理Sprague-Dawley(SD)大鼠2周,检测药物引起的代谢变化以及对肝脏内脂肪合成和脂肪酸氧化相关基因的影响.结果显示:Ola给药2周后,1.0 mg/kg和2.0 mg/kg处理组的体质量、血清甘油三酯(TG)、总胆固醇(TC)、肝脏及脂肪组织脂质水平增加,而低剂量组未出现明显的脂代谢副反应.此外,奥氮平显著上调肝脏固醇调节元件结合蛋白1(SREBP1),进而激活下游硬脂酰辅酶A去饱和酶1(Scd1)、乙酰辅酶A羧化酶1(Acc1)和脂肪酸合成酶(Fasn)等脂肪合成基因转录,下调过氧化物酶体增殖物激活受体α(PPARα)、肉毒碱棕榈酰基转移酶1A(CPT1A)和新型有机阳离子转运体2(OCTN2)等脂肪酸氧化因子.因此,奥氮平介导大鼠肝脏脂代谢紊乱存在显著剂量效应,该效应与组织内脂肪合成相关因子SREBP1的上调及脂肪酸氧化相关因子PPARα,CPT1A和OCTN2的下调相关.

Olanzapine(Ola),a first-line psychotherapeutic drug,imposes a high risk of abnormal glucose and lipid metabolism,but the mechanism is still unclear.The aim of this study was to simulate the clinical administration mode,compare the differences of lipid metabolism after short-term effect of different doses of Ola,and explore its possible mechanism.In this experiment,Sprague Dawley(SD)rats were continuously treated with different doses of Ola(0.25,0.5,1.0 or 2.0 mg/kg)for two weeks by oral administration.The metabolic changes in the serum induced by Ola were measured.Then,its effects on the genes related to fat synthesis and to fatty acid oxidation in the liver were investigated.After two-week administration of Ola,the 1.0 and 2.0 mg/kg treatment groups showed a significant increase in body weight,serum triglycerides(TG),total cholesterol(TC),fasting blood glucose(FBG)and liver lipid levels,while no severe secondary reactions of lipid metabolism were observed in the low-dose groups(0.25 and 0.5 mg/kg).In addition,Ola significantly upregulated the expression of the fatty acid synthesis transcription regulator SREBP1(sterol regulatory element binding protein 1)in the liver,and thus activated the transcription of the downstream fat synthesis genes:stearoyl CoA desaturase 1(Scd1),acetyl CoA carboxylase 1(Acc1),fatty acid synthase(Fasn).Ola-mediated lipid metabolism disorders have a significant dose effect,which is related to the up-regulation of fat synthesis-related factors SREBP1 and the down-regulation of fatty acid oxidation-related factors PPARα,CPT1A,OCTN2 in the liver.