Evaluation of Anti-atherosclerotic Activities of PPAR-α, PPAR-γ, and LXR Agonists in Hyperlipidemic Atherosclerosis-susceptible F(1)B Hamsters

Background: Fenofibrate, a PPAR-α agonist and rosiglitazone, a PPAR-γ agonist, reduce triglycerides and fatty acids in humans and in animal disease models. The efficacy of PPAR-α agonists in mouse model of human atherosclerosis disease has shown mixed results, and efficacy of PPAR-γ and liver X receptor (LXR) agonists has not been evaluated in cholesterol ester transfer protein (CETP) producing animal models.

Methods And Results: The efficacy of PPAR-α, PPAR-γ and LXR agonists on lipid lowering and antiatherosclerotic activities was studied in atherosclerosis-susceptible F(1)B hamster that showed greater responsiveness to dietary fat and cholesterol (HFHC) diet and increased severity of atherosclerosis compared to Golden Syrian (GS) hamsters (aortic lesion 0.3% in GS vs 5% in F(1)B). F(1)B hamsters were fed HFHC diet and simultaneously treated with fenofibrate, rosiglitazone, and T0901317 (a pan LXR agonist) for 8 weeks. Fenofibrate lowered triglycerides and LDL-C by >80%, rosiglitazone did not significantly impact plasma lipid levels, and as expected, T0901317 increased triglycerides by 3-fold and HDL-C by 50%. The lesions in the aortic arch area as measured by en face method, decreased by 81%, 38% and 35%, following fenofibrate, rosiglitazone, and T0901317 treatments, respectively. In F(1)B hamster regression model, fenofibrate decreased levels of triglycerides and LDL-C by >85%, and LDL-C by >70%, respectively, which resulted in ∼50% regression of aortic lesions compared to vehicle treated group, and ∼36% compared to baseline.

Conclusions: These results demonstrate that: (a) F(1)B hamster is more sensitive to developing diet-induced hyperlipidemia and atherosclerosis; and (b) the greater antiatherosclerotic efficacy of fenofibrate occurred primarily via reductions in proatherogenic lipoproteins. Thus, PPAR-α selective agonist shows a greater anti-atherosclerotic response compared to PPAR-γ and LXR agonists in diet-induced atherosclerosis-susceptible F(1)B hamster.