Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.
Liver X receptors (LXRs) alpha and beta are transcriptional regulators of cholesterol homeostasis and potential targets for the development of antiatherosclerosis drugs. However, the specific roles of individual LXR isotypes in atherosclerosis and the pharmacological effects of synthetic agonists remain unclear. Previous work has shown that mice lacking LXRalpha accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXRalpha(-/-)apoE(-/-) mice exhibit extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis. The phenotype of these mice suggests that the level of LXR pathway activation in macrophages achieved by LXRbeta and endogenous ligand is unable to maintain homeostasis in the setting of hypercholesterolemia. Surprisingly, however, a highly efficacious synthetic agonist was able to compensate for the loss of LXRalpha. Treatment of LXRalpha(-/-)apoE(-/-) mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXRalpha has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXRbeta.
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, California 90095-1662, USA.
Michelle N
MN
Bradley
Cynthia
C
Hong
Mingyi
M
Chen
Sean B
SB
Joseph
Damien C
DC
Wilpitz
Xuping
X
Wang
Aldons J
AJ
Lusis
Allan
A
Collins
Willa A
WA
Hseuh
Jon L
JL
Collins
Rajendra K
RK
Tangirala
Peter
P
Tontonoz
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000172:deficiency* / Q000378:metabolism*; D015195:Drug Design; D006706:Homeostasis / Q000235:genetics; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency* / Q000378:metabolism*
D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol