Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma.
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.
Li
Andrew C
AC
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0682, USA. acli@ucsd.edu
Binder
Christoph J
CJ
Gutierrez
Alejandra
A
Brown
Kathleen K
KK
Plotkin
Christine R
CR
Pattison
Jennifer W
JW
Valledor
Annabel F
AF
Davis
Roger A
RA
Willson
Timothy M
TM
Witztum
Joseph L
JL
Palinski
Wulf
W
Glass
Christopher K
CK
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D005487:Foam Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol