title: Evaluation of anti-atherosclerotic activities of PPAR-α, PPAR-γ, and LXR agonists in hyperlipidemic atherosclerosis-susceptible F(1)B hamsters.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Ltd., Mumbai, India. asrivastava@esperion.com
authors.forename: Rai Ajit K
authors.initials: RA
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D008647:Mesocricetus; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D013449:Sulfonamides / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D002784:Cholesterol; D005227:Fatty Acids; D011345:Fenofibrate; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D000077154:Rosiglitazone; D013449:Sulfonamides; D045162:Thiazolidinediones; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides