Abstract | OBJECTIVE: 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.
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Authors | Kazuhiro Nakaya, Junichiro Tohyama, Snehal U Naik, Hiroyuki Tanigawa, Colin MacPhee, Jeffrey T Billheimer, Daniel J Rader |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 31
Issue 6
Pg. 1276-82
(Jun 2011)
ISSN: 1524-4636 [Electronic] United States |
PMID | 21441141
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Apolipoprotein A-I
- Butyrates
- GW 7647
- Liver X Receptors
- Orphan Nuclear Receptors
- PPAR alpha
- Phenylurea Compounds
- Cholesterol
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Topics |
- Animals
- Apolipoprotein A-I
(physiology)
- Atherosclerosis
(prevention & control)
- Biological Transport
- Butyrates
(pharmacology)
- Cholesterol
(metabolism)
- Humans
- Liver X Receptors
- Macrophages
(metabolism)
- Mice
- Orphan Nuclear Receptors
(physiology)
- PPAR alpha
(agonists, physiology)
- Phenylurea Compounds
(pharmacology)
- Signal Transduction
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