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.
X-Ceptor Therapeutics, 4757 Nexus Center Drive, San Diego, CA 92121, USA.
Rajendra K
RK
Tangirala
Eric D
ED
Bischoff
Sean B
SB
Joseph
Brandee L
BL
Wagner
Robert
R
Walczak
Bryan A
BA
Laffitte
Chris L
CL
Daige
Diane
D
Thomas
Richard A
RA
Heyman
David J
DJ
Mangelsdorf
Xuping
X
Wang
Aldons J
AJ
Lusis
Peter
P
Tontonoz
Ira G
IG
Schulman
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