利拉鲁肽对高脂诱导肥胖小鼠肝脏脂代谢的影响

Effect of liraglutide on hepatic lipid metabolism in high-fat induced obese mice

目的:探讨利拉鲁肽调节高脂诱导肥胖小鼠肝脏脂代谢的作用机制。方法:将18只雄性健康C57BL/6小鼠分为3组:正常对照组(NC组)、肥胖对照组(OC组)和利拉鲁肽组,每组6只。NC组小鼠给予低脂饮食喂养,OC组以及利拉鲁肽组小鼠喂养12周高脂饲料以建立高脂诱导肥胖小鼠模型。之后,利拉鲁肽组小鼠连续7 d腹腔注射利拉鲁肽400μg·kg^(-1)·d^(-1),NC和OC组小鼠腹腔注射等体积生理盐水。检测脂肪组织及肝脏重量。检测小鼠体重、空腹血糖、葡萄糖耐量及胰岛素耐量,血清、肝脏甘油三酯(TG)及总胆固醇(TC)水平。采用酶联免疫吸附试验法检测小鼠血清胰岛素、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)水平。采用聚合酶链反应检测肝脏沉默信息调节因子1(SIRT-1)、过氧化物酶体增殖物激活受体γ共激活因子1α(PGC-1α)、磷酸烯醇式丙酮酸羧激酶(PEPCK)mRNA表达水平,Western blotting检测小鼠肝脏SIRT-1、PGC-1α及PEPCK蛋白的表达水平。组间比较采用单因素方差分析。结果:与NC组相比,OC组小鼠的体重、脂肪重量、空腹血糖和空腹胰岛素水平均升高(P<0.05),葡萄糖和胰岛素耐量水平降低(P<0.05),血清TG、TC、IL-6、TNF-α水平及肝脏TG、肝脏TC、肝脏重量均升高(P<0.05),肝脏SIRT-1、PGC-1α、PEPCK mRNA及蛋白表达水平均降低(P<0.05)。与OC组相比,利拉鲁肽组小鼠的体重、脂肪重量、空腹血糖和空腹胰岛素水平均降低(P<0.05),葡萄糖和胰岛素耐量水平升高(P<0.05),血清胰岛素、IL-6、TNF-α及TG水平均降低(P<0.05),肝脏脂质降低(P<0.05),肝脏SIRT-1、PGC-1α、PEPCK mRNA及蛋白水平均升高(P<0.05)。结论:利拉鲁肽能够改善高脂饮食诱导肥胖小鼠的糖脂代谢,提高肝脏脂肪酸氧化,减少肝脏脂肪蓄积,其机制可能与激活肝脏SIRT-1/PGC-1α/PEPCK通路有关。

Objective To investigate of the mechanism of liraglutide regulation of high-fat-induced hepatic lipid metabolism in mice.Methods Eighteen healthy male C57BL/6 mice were randomly divided into three groups:normal control group(NC group),obesity control group(OC group)and liraglutide group(six mice in each group).Mice in NC group were fed with low-fat diet,and mice in OC group and liraglutide group were fed with high-fat diet for 12 weeks to establish the high-fat induced obesity mouse model.Then,liraglutide group was intraperitoneally injected with 400μg·kg^(-1)·d^(-1) for 7 days,equal volumes of saline were injected intraperitoneally into the NC and OC groups.Adipose tissue and liver weight were measured.Body weight,fasting blood glucose,glucose tolerance and insulin resistance,serum and liver triglyceride(TG)and total cholesterol(TC)levels were measured.Serum insulin,interleukin 6(IL-6)and tumor necrosis factorα(TNF-α)levels were measured by enzyme-linked immunosorbent assay.The mRNA levels of silent information regulator 1(SIRT-1),peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α)and phosphoenolpyruvate carboxykinase(PEPCK)in liver were detected by polymerase chain reaction.The protein expression levels of mouse liver SIRT-1,PGC-1αand PEPCK,were detected by Western blotting.One-way analysis of variance(ANOVA)was used for comparison between groups.Results Compared with NC group,in OC group,body weight,fat weight,fasting blood glucose and fasting insulin levels were increased(P<0.05),glucose and insulin tolerance levels were decreased(P<0.05),serum TG,TC,IL-6 and TNF-αlevels and liver TG,liver TC and liver weight were increased(P<0.05),however,liver SIRT-1,PGC-1α,PEPCK mRNA and protein levels were decreased(P<0.05).Compared with the OC group,in the liraglutide group,body weight,fat weight,fasting blood glucose and fasting insulin levels were decreased(P<0.05),glucose and insulin tolerance levels were increased(P<0.05),serum insulin,IL-6,TNF-αand triglycerides were significantly decreased(P<0.05),liver lipids were reduced(P<0.05),however,liver SIRT-1,PGC-1α,PEPCK mRNA and protein levels were significantly increased(P<0.05).Conclusions Liraglutide improved glucolipid metabolism,increased hepatic fatty acid oxidation and reduced hepatic fat accumulation in high-fat diet-induced obese mice,and the mechanism might be related to activation of hepatic SIRT-1/PGC-1α/PEPCK pathway.