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PMID: 15578089 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma.

The Journal of clinical investigation ·Vol. 114 ·No. 11 ·2004-12-00 ·Pages 1564-76

Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK

Abstract

PPARalpha, beta/delta, and gamma regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARalpha, beta, and gamma agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR(-/-)) mice. Like the PPARgamma agonist, a PPARalpha-specific agonist strongly inhibited atherosclerosis, whereas a PPARbeta-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARalpha and PPARgamma agonists, but not the PPARbeta agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARalpha and PPARgamma agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARalpha required LXRs, activation of PPARgamma reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.

MeSH Terms
Animals Aorta/cytology,metabolism,pathology Arteriosclerosis/metabolism,pathology Cholesterol/metabolism Cholesterol, Dietary DNA-Binding Proteins Foam Cells/physiology Gene Expression Regulation Humans Liver X Receptors Macrophages, Peritoneal/cytology,metabolism Male Mice Mice, Inbred Strains Mice, Knockout Orphan Nuclear Receptors PPAR alpha/agonists,genetics,metabolism PPAR delta/agonists,genetics,metabolism PPAR gamma/agonists,genetics,metabolism PPAR-beta/agonists,genetics,metabolism Receptors, Cytoplasmic and Nuclear/genetics,metabolism Receptors, LDL/genetics,metabolism Triglycerides/metabolism
Chemicals
Cholesterol, Dietary DNA-Binding Proteins Liver X Receptors Orphan Nuclear Receptors PPAR alpha PPAR delta PPAR gamma PPAR-beta Receptors, Cytoplasmic and Nuclear Receptors, LDL Triglycerides Cholesterol
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Li Andrew C
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0682, USA. acli@ucsd.edu
Binder Christoph J
Gutierrez Alejandra
Brown Kathleen K
Plotkin Christine R
Pattison Jennifer W
Valledor Annabel F
Davis Roger A
Willson Timothy M
Witztum Joseph L
Palinski Wulf
Glass Christopher K
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI18730
Email
acli@ucsd.edu
Published
2004-12-00
Pages
1564-76
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC529277
Subset
IM
Grants
NHLBI NIH HHS · P50 HL056989 · United States
NHLBI NIH HHS · HL-03625 · United States
NHLBI NIH HHS · HL-56989 · United States
Corrections
CommentIn
PMID: 15578084
External Links
PubMed source DOI: 10.1172/JCI18730 PMC Full Text View journal details
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