Synthetic LXR ligand inhibits the development of atherosclerosis in mice.
The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR(-/-) mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR(-/-) and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.
Joseph
Sean B
SB
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095-1662, USA.
McKilligin
Elaine
E
Pei
Liming
L
Watson
Michael A
MA
Collins
Alan R
AR
Laffitte
Bryan A
BA
Chen
Mingyi
M
Noh
Grace
G
Goodman
Joanne
J
Hagger
Graham N
GN
Tran
Jonathan
J
Tippin
Tim K
TK
Wang
Xuping
X
Lusis
Aldons J
AJ
Hsueh
Willa A
WA
Law
Ronald E
RE
Collins
Jon L
JL
Willson
Timothy M
TM
Tontonoz
Peter
P
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins; D005260:Female; D008024:Ligands; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D002784:Cholesterol