title: Peroxisome proliferator-activated receptor-α activation promotes macrophage reverse cholesterol transport through a liver X receptor-dependent pathway.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Kazuhiro
authors: K
authors: Nakaya
authors: Junichiro
authors: J
authors: Tohyama
authors: Snehal U
authors: SU
authors: Naik
authors: Hiroyuki
authors: H
authors: Tanigawa
authors: Colin
authors: C
authors: MacPhee
authors: Jeffrey T
authors: JT
authors: Billheimer
authors: Daniel J
authors: DJ
authors: Rader
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology; D050197:Atherosclerosis / Q000517:prevention & control; D001692:Biological Transport; D002087:Butyrates / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D016632:Apolipoprotein A-I; D002087:Butyrates; C453899:GW 7647; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D010671:Phenylurea Compounds; D002784:Cholesterol