二甲双胍治疗氯氮平所致脂质代谢紊乱的实验研究

The effects of metformin on lipid metabolism disorder caused by clozapine in rats

目的观察大鼠中二甲双胍(metformin,MET)对氯氮平(clozapine,CLO)所致脂质代谢紊乱的影响,探讨防治非典型抗精神病药物所致脂质代谢紊乱的新策略。方法 SD大鼠随机分为对照组、CLO组、CLO+MET组、CLO+A769622组等4组,每组9只。相应组分别通过腹腔注射给予CLO(15 mg/kg),灌胃给予MET(30 mg/kg)或A769662(20 mg/kg),对照组通过腹腔注射给予生理盐水,连续给药4周。每日记录大鼠体重与食物摄取量。4周末测定大鼠血清和肝脏中各脂质代谢物含量,并检测腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK)磷酸化水平,以及脂肪酸合成关键酶、胆固醇代谢关键酶mRNA表达水平。结果 CLO组、CLO+MET组、CLO+A769662组相比对照组大鼠体重略有减少(P<0.05),但摄食量差异无统计学意义(P>0.05)。CLO组相比对照组血清中甘油三酯(triglyceride, TG)、总胆固醇(total cholesterol, TC)、血清游离脂肪酸(free fatty acid, FFA)水平和肝脏中TG、TC水平增加(P<0.01),AMPK磷酸化水平则减少(P<0.01)。与其他3组相比,CLO组1型胆固醇调节元件结合蛋白(sterol regulatory element-binding protein type 1,SREBP1)mRNA、乙酰辅酶A羧化酶(acetyl CoA carboxylase 1c,ACC1)、脂肪酸合成酶(fatty acid synthetase,FAS)mRNA、SREBP2 mRNA、羟甲基戊二酰辅酶A还原酶(hydroxymethyl glutaryl coenzyme A reductase, HMGCR)mRNA、低密度脂蛋白受体(low density lipoprotein receptor, LDLR)mRNA表达增加(P<0.01)。CLO+MET组相比对照组血清中TG、FFA水平和肝脏中TG水平增加(P<0.01),血清中TC水平也增加(P<0.05),AMPK磷酸化水平、SREBP1 mRNA、ACC1 mRNA、HMGCR mRNA表达增加(P<0.01),FAS mRNA表达也增加(P<0.05)。CLO+A769662相比对照组血清中TG、FFA水平和肝脏中TG水平增加(P<0.01),肝脏中TC水平增加(P<0.05),AMPK磷酸化水平、SREBP1 mRNA、ACC1 mRNA、FAS mRNA、HMGCR mRNA表达增加(P<0.01),SREBP2 mRNA、LDLR mRNA表达也增加(P<0.05)。结论 CLO通过诱导肝脏中SREBP的表达而促进脂质生成,而MET可能通过抑制SREBP通路辅助治疗AAPD引起的脂质代谢副反应。

Objective To investigate the effects of Metformin(MET)on lipid metabolism disorder caused by clozapine(CLO)in rats and to explore the prevention and treatment for lipid metabolic disorder caused by atypical antipsychotic drugs.Methods SD rats were randomly divided into four groups:control,CLO,CLO+MET and CLO+A769622.Each group consisted of 9 rats.CLO was given to rats at a dose of 15 mg/kg ip,MET and A769662 were administered via intragastric administration at dose of 30 mg/kg and 20 mg/kg respectively for 4 weeks.The control group was given saline.The weight and food intake of the rats were recorded every day.The content of serum and liver lipid metabolites were assessed.Western-blot and PCR were used to detect the phosphorylation levels of AMPK,and the mRNA expression level of key enzymes include fatty acids and cholesterol,respectively.Results Compared with the control group,rats body weight of CLO,CLO+MET,CLO+A769662 group slightly decreased(P<0.05)while food intake remained unchanged after treatment.Compared with the control group,TG,TC,FFA levels in serum and TG and TC levels in liver were significantly increased in the CLO group(P<0.01),while the phosphorylation level of AMPK was decreased(P<0.01).Compared with the other three groups,the expression of SREBP1 mRNA,ACC1 mRNA,FAS mRNA,SREBP2 mRNA,HMGCR mRNA and LDLR mRNA were significantly increased in the CLO group(P<0.01).Compared with the control group,TG and FFA levels in serum were significantly increased(P<0.01)in CLO+MET group,TC level in serum was also significantly increased(P<0.05),the phosphorylation level of AMPK,SREBP1 mRNA,ACC1 mRNA and HMGCR mRNA expression were significantly increased(P<0.01),and the expression of FAS mRNA was also significantly increased in CLO+MET group(P<0.05).Compared with the control group,TG,FFA levels in serum and TG level in liver were significantly increased in CLO+A769662 group(P<0.01),TC level in liver was also significantly increased in CLO+A769662 group(P<0.05).AMPK phosphorylation level,SREBP1 mRNA,ACC1 mRNA,FAS mRNA and HMGCR mRNA expression were significantly increased(P<0.01),and SREBP2 mRNA and LDLR mRNA expression also increased in CLO+A769662 group(P<0.05).Conclusions CLO promotes lipid production by inducing the expression of SREBP in the liver,and MET may assist in the treatment of lipid metabolic side effects of AAPD by inhibiting the SREBP pathway.