Peroxisome proliferator-activated receptor-alpha activation promotes macrophage reverse cholesterol transport through a liver X receptor-dependent pathway. Arteriosclerosis, Thrombosis, and Vascular Biology 31:1276e1282

Objective—Peroxisome proliferator-activated receptor- (PPAR) activation has been shown in vitro to increase macrophage cholesterol efflux, the initial step in reverse cholesterol transport (RCT). However, it remains unclear whether PPAR activation promotes macrophage RCT in vivo. Methods and Results—We demonstrated that a specific potent PPAR agonist GW7647 inhibited atherosclerosis and promoted macrophage RCT in hypercholesterolemic mice expressing the human apolipoprotein A-I (apoA-I) gene. We compared the effect of GW7647 on RCT in human apoA-I transgenic (hA-ITg) mice with wild-type mice and showed that the PPAR agonist promoted RCT in hA-ITg mice to a much greater extent than in wild-type mice, indicating that human apoA-I expression is important for PPAR-induced RCT. We further investigated the dependence of the macrophage PPAR–liver X receptor (LXR) pathway on the promotion of RCT by GW7647. Primary murine macrophages lacking PPAR or LXR abolished the ability of GW7647 to promote RCT in hA-ITg mice. In concert, the PPAR agonist promoted cholesterol efflux and ATP binding cassette transporter A1/G1 expression in primary macrophages, and this was also by the PPAR-LXR pathway. Conclusion—Our observations demonstrate that a potent PPAR agonist promotes macrophage RCT in vivo in a manner that is enhanced by human apoA-I expression and dependent on both macrophage PPAR and LXR expression. (Arterioscler Thromb Vasc Biol. 2011;31:1276-1282.