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Identification of macrophage liver X receptors as inhibitors of atherosclerosis.

Abstract
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.
AuthorsRajendra 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
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 18 Pg. 11896-901 (Sep 03 2002) ISSN: 0027-8424 [Print] United States
PMID12193651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
Topics
  • Animals
  • Arteriosclerosis (physiopathology)
  • DNA-Binding Proteins
  • Female
  • Liver X Receptors
  • Macrophages (metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear (genetics, metabolism, physiology)
  • Reverse Transcriptase Polymerase Chain Reaction

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