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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (31142)	8/25/2002 11:00:19 AM
From: tuck	Read Replies (3) \| Respond to of 32384

>>Published online before print August 22, 2002 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.182199799 Medical Sciences 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 ¶, and Ira G. Schulman ¶ X-Ceptor Therapeutics, 4757 Nexus Center Drive, San Diego, CA 92121; Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, and Department of Medicine, University of California, Los Angeles, CA 90095; and Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050 Edited by Jan L. Breslow, The Rockefeller University, New York, NY, and approved July 1, 2002 (received for review April 4, 2002) Recent studies have identified the liver X receptors (LXR and LXRß) 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. -------------------------------------------------------------------------------- ¶To whom reprint requests may be addressed. E-mail: ischulman@x-ceptor.com.<< Cheers, Tuck