title: Anti-hyperlipidemic and insulin sensitizing activities of fenofibrate reduces aortic lipid deposition in hyperlipidemic Golden Syrian hamster.
abstract: Cholesterol ester transfer protein (CETP) and apolipoprotein (apo) E are important in peroxisome proliferation activated receptor-α (PPAR-α)-mediated regulation of lipoprotein metabolism. Therefore, popularly used apolipoprotein E knockout mice are not suitable to evaluate PPAR-α agonists. In this study, we aimed to: a) evaluate hamster as a model for insulin resistance, hyperlipidemia and atherosclerosis; and b) investigate the effect of a PPAR-α activator, fenofibrate, in this model. A high fat high cholesterol (HFHC) diet increased serum cholesterol and triglycerides, but inclusion of fenofibrate in the diet decreased cholesterol and proatherogenic lipoproteins, VLDL and LDL, in a time-dependent manner. Concomitantly, serum levels of triglycerides also decreased. These reductions were attributed, in part, to the down-regulation of lipogenic genes and upregulation of lipoprotein lipase. The HFHC diet caused body weight gain and mild insulin resistance, both of which were prevented following the treatments with fenofibrate. Insulin resistance was further investigated in high fructose-fed hamsters. Fenofibrate prevented both hyperinsulinemia and hypertriglyceridemia. The insulin sensitizing activity of fenofibrate appeared to occur via reductions in protein tyrosine phophatase-1B. To determine whether lowering of lipids by fenofibrate treatment contributed to the reduced risks of developing atherosclerosis in hyperlipidemic hamsters, we measured lipid deposition in the aorta. Our results showed that fenofibrate treatment reduced aortic lipid deposition by 70%. These findings suggest that hamster may be an adequate animal model to evaluate the efficacy of lipid lowering, insulin sensitizing and antiatherosclerotic agents. We also show that fenofibrate is an effective antiatherosclerotic agent in hyperlipidemic hamster model.
authors.affiliation: Department of Pharmacology, Esperion Therapeutics Inc., Plymouth, MI 48170, USA. asrivastava@esperion.com
authors.forename: Rai Ajit K
authors.initials: RA
authors.lastname: Srivastava
authors.forename: Shirley
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000517:prevention & control; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage / Q000097:blood; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008647:Mesocricetus; D023421:Models, Animal; D047493:PPAR alpha / Q000819:agonists; D015430:Weight Gain
chemical_list: D004041:Dietary Fats; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D002784:Cholesterol; D011345:Fenofibrate