非诺贝特保护非酒精性脂肪性肝病小鼠胰岛素抵抗作用机制的探讨  

Protective effects of fenofibrate on insulin resistance in mice of nonalcoholic fatty liver disease and its partly mechanisms of action

作　　者：沈馨茹[1] 鲁云霞[2] 章秋[1] 

机构地区：[1]安徽医科大学第一附属医院内分泌科,合肥230022 [2]安徽医科大学生物化学教研室,合肥230032

出　　处：《安徽医科大学学报》2014年第6期721-725,共5页Acta Universitatis Medicinalis Anhui

基　　金：安徽省自然科学基金(编号:1208085MH168;1308085MH154);安徽医科大学博士启动基金(编号:XJ201013)

摘　　要：目的研究非诺贝特改善非酒精性脂肪性肝病(NAFLD)小鼠的胰岛素抵抗是否与内质网应激(ERS)有关。方法采用高热量高胆固醇饮食(HCD)建立NAFLD小鼠模型,非诺贝特40 mg/(kg·d)灌胃治疗2周,葡萄糖耐量试验(GTT)和胰岛素耐量试验(ITT)分析胰岛素抵抗的改善作用,检测血清血脂和丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)指标,HE及油红O染色观察肝脏组织的病理学变化,Real-time PCR和Western blot法检测过氧化物酶体增殖物激活受体α(PPARα)、ERS标志物葡萄糖调节蛋白78(GRP78)和转录因子GADD153(CHOP)的表达。结果与正常饮食(SCD)组相比,HCD组小鼠胰岛素抵抗明显,血清三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)显著升高(P<0.01,P<0.05),高密度脂蛋白胆固醇(HDL-C)明显降低(P<0.01),肝细胞内有大小不等的脂滴形成,可见气球样变的肝细胞及炎性细胞浸润;PPARα、GRP78 mRNA及蛋白表达显著降低,CHOP mRNA及蛋白表达显著升高。与HCD组相比,HCD+非诺贝特(HCF)组小鼠血清TG明显降低(P<0.05),肝细胞脂滴含量、变性肝细胞及浸润的炎细胞明显减少,PPARα、GRP78mRNA及蛋白表达明显升高,CHOP mRNA及蛋白表达显著降低(P<0.05)。结论非诺贝特有明显的改善NAFLD小鼠胰岛素抵抗、降低TG的作用,这可能与激活PPARα及减轻ERS有关。Objective To study whether the protective effects of fenofibrate on insulin resistance in mice of nonal-coholic fatty liver disease（NAFLD） are related to endoplasmic reticulum stress （ERS）. Methods Male C57BL/6 mice were fed with high-calorie and high-cholesterol diet （ HCD） to induce a model of NAFLD, then one of those two groups from HCD was treated with fenofibrate 40 mg/（ kg ＆#183; d ） for 2 weeks （ HCF ） . Glucose tolerance test （GTT） and insulin tolerance test （ITT） were used to analyze the improvement on insulin resistance. The serum levels of triglyceride （ TG） , total cholesterol （ TC） , high density lipoprotein-cholesterol （ HDL-C） , low density lip-oprotein-cholesterol （ LDL-C） , alanine aminotransferase （ ALT） and aspartic transaminase （ AST） were detected. The pathological changes of livers were detected with HE and Oil Red O staining, the mRNA and protein expression of peroxisome proliferator-activated receptorα（ PPARα） , glucose regulated protein 78 （ GRP78 ） and transcription factors GADD153 （ CHOP） were detected with real-time quantification PCR and Western blot analysis respectively. Results Compared with the SCD mice, the HCD mice showed significant insulin resistance, higher serum levels of TG, TC and LDL-C （P〈0. 01, P〈0. 05）, lower serum level of HDL-C （P〈0. 01）, micro-and macrovesicular steatosis, ballooned hepatocytes and infiltration of inflammatory cells were observed in the liver, the expressions of PPARα and GRP78 at mRNA and protein levels were decreased （P〈0. 05）, however, the expressions of CHOP at mRNA and protein levels were increased （ P〈0 . 05 ） . Fenofibrate intervention significantly improved insulin resist-ance and decreased the serum level of TG （ P〈0. 05 ） . Fenofibrate also alleviated hepatic steatosis and inflammato-ry infiltration, and increased the mRNA and protein expressions of PPARα and GRP78, decreased the mRNA and protein expression of CHOP （ P〈0 . 05 ） . Conc

关 键 词：非诺贝特 非酒精性脂肪性肝病 胰岛素抵抗 内质网应激 PPARΑ PPARΑ 

分 类 号：R332[医药卫生—人体生理学] R965.1[医药卫生—基础医学]