Identification of macrophage liver X receptors as inhibitors of atherosclerosis

Rajendra K. Tangirala, Eric D. Bischoff, Sean B. Joseph, Brandee L. Wagner, Robert Walczak, Bryan A. Laffitte, Chris L. Daige, Diane Thomas, Richard A. Heyman, David J. Mangelsdorf, Xuping Wang, Aldons J. Lusis, Peter Tontonoz, Ira G. Schulman

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)11896-11901
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number18
DOIs
StatePublished - Sep 3 2002

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Tangirala, R. K., Bischoff, E. D., Joseph, S. B., Wagner, B. L., Walczak, R., Laffitte, B. A., Daige, C. L., Thomas, D., Heyman, R. A., Mangelsdorf, D. J., Wang, X., Lusis, A. J., Tontonoz, P., & Schulman, I. G. (2002). Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America, 99(18), 11896-11901. https://doi.org/10.1073/pnas.182199799