Liver X receptors (LXR␣ (NR1H3) and LXR (NR1H2)) 1 are recently described members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are important in the regulation of genes that govern cholesterol homeostasis in the liver and cholesterol efflux from peripheral tissues. LXRs are bound by and activated by specific cholesterol metabolites, including oxysterols, and regulate the expression of target genes by binding to specific promoter response elements (LXREs) in association with the obligate heterodimerization partner, retinoid X receptor (RXR), the receptor for 9-cis-retinoic acid (9cRA) (1). Natural ligands for LXR include 22(R)-hydroxycholesterol (22(R)-HC), 24(S),25-epoxycholesterol, and 25-hydroxycholesterol (2-4), compounds that have been found free in serum and in association with atherogenic oxidized low density lipoprotein (oxLDL) particles (5-7). In the liver, LXR␣ serves as a sterol sensor and regulates the expression of genes that influence cholesterol metabolism and homeostasis, including the genes encoding cholesterol 7␣-hydroxylase, which controls the cholesterol/bile acid synthetic pathway, and sterol regulatory element-binding protein-1c, a key transcription factor that regulates expression of genes important in fatty acid biosynthesis (6, 8, 9 -11). Studies using lxr null mice have shown that LXR␣ is essential for normal cholesterol homeostasis and secretion of excess cholesterol in vivo (9).Recent work has shown that LXR␣ plays a fundamental role in macrophage biology by regulating cholesterol efflux from lipid-loaded cells. This is manifested by LXR␣-mediated induction of genes encoding the ATP-binding cassette proteins ABC-1 and ABCG1, which encode plasma membrane-associated reverse cholesterol transport proteins that mediate cholesteryl ester and free cholesterol efflux from monocytes and lipid-loaded macrophages (12-15). Effluxed cholesterol is subsequently delivered to extracellular acceptors, especially high density lipoprotein/ApoE, and transported back to the liver where it is converted to bile acids and excreted (1). The key role of LXR as a master regulator in the overall process governing cholesterol efflux and reducing intracellular cholesterol levels is underscored by the findings that the genes encoding ApoE, which is necessary for high density lipoprotein formation is also a transcriptional target of LXR (16). The pivotal role of LXR␣ in regulating reverse cholesterol transport in macrophages is of particular disease relevance, because lipid accumulation in these cells, through the uptake of oxLDL, is of fundamental importance to the etiology and pathogenesis of atherogenesis and atherosclerosis and other chronic inflammatory diseases. oxLDL particles accumulate in macrophages that have infiltrated the arterial intimal space, subsequently developing into lipid-loaded foam cells that comprise the characteristic fatty streak of early atherosclerotic lesions (17). In this context, LXR␣, by reducing intracellular cholesterol and lipid accumul...