Protective effects of fenofibrate on insulin resistance in mice of nonalcoholic fatty liver disease and its partly mechanisms of action / 安徽医科大学学报

ABSTRACT

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.