Peroxisome Proliferator-Activated Receptor-α Activation Promotes Macrophage Reverse Cholesterol Transport Through a Liver X Receptor–Dependent Pathway

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 6; pp. 1276 - 1282
• Main Authors: Nakaya, Kazuhiro, Tohyama, Junichiro, Naik, Snehal U, Tanigawa, Hiroyuki, MacPhee, Colin, Billheimer, Jeffrey T, Rader, Daniel J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.06.2011; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoprotein A-I - physiology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Atherosclerosis - prevention & control; Biological and medical sciences; Biological Transport; Blood and lymphatic vessels; Butyrates - pharmacology; Cardiology. Vascular system; Cholesterol - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Humans; Liver X Receptors; Macrophages - metabolism; Medical sciences; Mice; Orphan Nuclear Receptors - physiology; Phenylurea Compounds - pharmacology; PPAR alpha - agonists; PPAR alpha - physiology; Signal Transduction; Digestive system; Liver; Lipids; Cardiovascular disease; Lipoprotein; Cholesterol; Peroxisome proliferator; Vascular disease; macrophages; Atherosclerosis; Transport; ABC transporter; cholesterol-lowering drugs; lipoproteins; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.111.225383

OBJECTIVE—Peroxisome proliferator-activated receptor-α (PPARα) activation has been shown in vitro to increase macrophage cholesterol efflux, the initial step in reverse cholesterol transport (RCT). However, it remains unclear whether PPARα activation promotes macrophage RCT in vivo. METHODS AND RESULTS—We demonstrated that a specific potent PPARα 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 PPARα 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 PPARα-induced RCT. We further investigated the dependence of the macrophage PPARα–liver X receptor (LXR) pathway on the promotion of RCT by GW7647. Primary murine macrophages lacking PPARα or LXR abolished the ability of GW7647 to promote RCT in hA-ITg mice. In concert, the PPARα agonist promoted cholesterol efflux and ATP binding cassette transporter A1/G1 expression in primary macrophages, and this was also by the PPARα-LXR pathway. CONCLUSION—Our observations demonstrate that a potent PPARα agonist promotes macrophage RCT in vivo in a manner that is enhanced by human apoA-I expression and dependent on both macrophage PPARα and LXR expression.