Identification of macrophage liver X receptors as inhibitors of atherosclerosis.
Recent studies have identified the liver X receptors (LXR alpha and LXR beta) as important regulators of cholesterol metabolism and transport. LXRs control transcription of genes critical to a range of biological functions including regulation of high density lipoprotein cholesterol metabolism, hepatic cholesterol catabolism, and intestinal sterol absorption. Although LXR activity has been proposed to be critical for physiologic lipid metabolism and transport, direct evidence linking LXR signaling pathways to the pathogenesis of cardiovascular disease has yet to be established. In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. Our results demonstrate that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identify LXRs as targets for intervention in cardiovascular disease.
Tangirala
Rajendra K
RK
X-Ceptor Therapeutics, 4757 Nexus Center Drive, San Diego, CA 92121, USA.
Bischoff
Eric D
ED
Joseph
Sean B
SB
Wagner
Brandee L
BL
Walczak
Robert
R
Laffitte
Bryan A
BA
Daige
Chris L
CL
Thomas
Diane
D
Heyman
Richard A
RA
Mangelsdorf
David J
DJ
Wang
Xuping
X
Lusis
Aldons J
AJ
Tontonoz
Peter
P
Schulman
Ira G
IG
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D004268:DNA-Binding Proteins; D005260:Female; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear