Identification of Macrophage Liver X Receptors as Inhibitors of Atherosclerosis

Recent studies have identified the liver X receptors (LXRα and LXRβ) 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 chole...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-09, Vol.99 (18), p.11896-11901
Main Authors: Tangirala, Rajendra K., Bischoff, Eric D., Joseph, Sean B., Wagner, Brandee L., Walczak, Robert, Laffitte, Bryan A., Daige, Chris L., Thomas, Diane, Heyman, Richard A., Mangelsdorf, David J., Wang, Xuping, Lusis, Aldons J., Tontonoz, Peter, Schulman, Ira G.
Format: Article
Language:English
Subjects:
Animals
Arteriosclerosis - physiopathology
Atherosclerosis
Biological Sciences
Bone marrow
Bone marrow transplantation
Cholesterols
DNA-Binding Proteins
Female
Lesions
Lipids
Liver X Receptors
Macrophages
Macrophages - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Orphan Nuclear Receptors
Receptors
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Cytoplasmic and Nuclear - physiology
Reverse Transcriptase Polymerase Chain Reaction
Transplantation
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Summary:Recent studies have identified the liver X receptors (LXRα and LXRβ) 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.182199799