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、GRP78 mRNA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 · 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 ) . Conclusion Fenofibrate significantly improves insulin resistance and de-creases the serum level of TG in NAFLD mice, which may be related to activating PPARα and relieving ERS.
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