Abstract 1611: PPAR α Agonism Promotes Reverse Cholesterol Transport in a Macrophage PPAR α and Liver X Receptor Dependent Manner
Peroxisome proliferator activated receptor α (PPARα), a ligand-activated transcription factor, regulates transcription of genes involved in metabolism. PPARα agonists have been reported to promote cholesterol efflux from macrophages in vitro. These studies were designed to test the hypothesis that PPARα agonists act to reduce atherosclerosis by enhancing reverse cholesterol transport (RCT) in vivo. Treatment of an atherosclerosis-susceptible mouse model, low-density lipoprotein receptor−/−/apobec−/−/human apoA-I transgenic mice, with the PPARα agonist GW7647 for 24 weeks resulted in significantly less atherosclerosis as compared to control mice. To determine the effect of GW7647 on macrophage RCT, wild-type (WT), human apoA-I transgenic (hA-I tg) mice and hA-I tg/CETP expressing mice were treated with GW7647 or vehicle for 14 days and then injected intraperitoneally with [3H]-cholesterol-labeled and cholesterol loaded macrophages and monitored for the appearance of [3H]-tracer in plasma, liver and feces. In all three mouse models, GW7647 significantly promoted macrophage RCT. To investigate the requirement for macrophage PPARα, an RCT study was performed in GW7647-treated mice using bone marrow macrophages (BMM) derived from WT or PPARα deficient mice and showed that GW7647 promoted RCT from WT but not PPARα deficient macrophages. It has been suggested that PPARα promotes cholesterol efflux via upregulation of LXR. Indeed, GW7647 promoted RCT from WT but not LXR α/β deficient macrophages. In conclusion, treatment with the PPARα agonist GW7647 reduced atherosclerosis and promoted macrophage RCT in vivo in a PPARα and LXR dependent manner.