Abstract 419: Human ApoB100/CETP Transgenic Mouse is a Useful Animal Model for Evaluation of HDL-C Elevation and Suppression of Atherosclerosis by Peroxisome Proliferator-Activated Receptor Delta Agonist

Abstract

PPARδ is one of the transcription factors that regulate lipid metabolism. Recently, PPARδ agonists have been reported to induce the elevation of plasma HDL-C levels in obese mice, rhesus monkeys as well as humans, indicating their potentials as a new class of HDL-C raising agent. In addition, anti-atherosclerotic effects of PPARδ agonists were reported in LDLR-KO and ApoE-KO mice. In these mice, however, the lipoprotein profiles are greatly different from those in humans in terms of the deficiency in CETP and ApoB100, and thus the anti-inflammatory effects were regarded as a main anti-atherosclerotic mechanism of PPARδ agonists. It has been reported that human ApoB100/CETP transgenic (hApoB100/CETP-Tg) mice have similar lipoprotein profiles with humans. In this study, we used hApoB100/CETP-Tg mice placed under a western diet for evaluation of GW501516, one of the most potent and selective PPARδ agonists, in order to investigate the linkage between HDL-C elevation and anti-atherosclerotic potency. For evaluation of plasma HDL-C levels, the hApoB100/CETP-Tg mice were orally treated with GW501516 for 1 week and its potency was compared with fenofibrate, a PPARα agonist used in the clinic. For evaluation of the anti-atherosclerotic effect, the mice were orally treated with GW501516 for 18 weeks and atherosclerosis at the aortic valves was determined by cross-sectional lesion analysis. Serum lipoprotein parameters were periodically monitored and lipoprotein profiles were analyzed by FPLC method. Treatment with GW501516 resulted in significant elevation of plasma HDL-C levels with more potency compared to fenofibrate (24% and 15% elevation at 10mg/kg, respectively). Serum apoA-I was also increased by the similar ratio as HDL-C, and the particle size of HDL was not changed, suggesting that the numbers of HDL particle are increased by GW501516. Long term treatment of GW501516 (3 and 10 mg/kg) resulted in dose-dependent suppression of atherosclerosis (42 and 57% inhibition, respectively) with a strong correlation with HDL-C elevation (p<0.001). By using hApoB100/CETP-Tg mice, PPARδ was confirmed as a promising target of anti-atherosclerotic therapy as a new class of HDL-C raising agent.