Fenofibrate ameliorates diabetic and dyslipidemic profiles in KKAy mice partly via down-regulation of 11β-HSD1, PEPCK and DGAT2.: Comparison of PPARα, PPARγ, and liver x receptor agonists

Fenofibrate and rosiglitazone are prescribed to treat hypertriglyceridemia and diabetes, respectively. Since fenofibrate improves lipid profile in diabetic patients and improves insulin resistance in animal models, we examined the mechanism of antidiabetic effects of fenofibrate in KKAy mouse, an animal model of diabetes and dyslipidemia. KKAy mice were treated with fenofibrate, rosiglitazone, liver x receptor agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), and a combination of fenofibrate and T090317 for 2 weeks. Fenofibrate lowered serum triglycerides by 90% and free fatty acid (FFA) by 50% via inhibition of hepatic fatty acid synthesis. Fenofibrate also prevented T0901317-induced increases of triglycerides by dampening T090317-mediated sterol response element binding protein 1c (SREBP1c) up-regulation. Glucose lowering was comparable (~ 40%) in fenofibrate and rosiglitazone treated mice. T090317 also showed mild reduction in serum glucose, in part, via down-regulation of phosphoenol pyruvate carboxykinase (PEPCK). Combining fenofibrate with T0901317 caused greater reduction in serum glucose, suggesting an additive effect. The mechanism of lipid and glucose lowering in KKAy mice was examined. Liver PEPCK showed down-regulation in all treatment groups with fenofibrate showing greater effects. Combination of fenofibrate with T090317 showed additive effects on PEPCK down-regulation. Fenofibrate decreased hepatic diacyl glycerol acyl transferase 2 (DGAT2) mRNA leading to reduction in triglyceride synthesis. Most importantly, fenofibrate down regulated expression of hepatic and adipose 11beta hydroxysteroid dehydrogenase (11β-HSD1) gene, which contributed in attenuating diabetic state. Thus, amelioration of antidiabetic and hyperlipidemic state by fenofibrate in KKAy mice occurred via down-regulation of DGAT2, PEPCK and 11β-HSD1. It is also shown that the undesirable lipogenic effects of T090317 could be dampened by fenofibrate.