Abstract 3619: A Novel Tissue Selective LXR Ligand, WYE-672
LXR nuclear receptors regulate cholesterol homeostasis via the modulation of genes involved in cholesterol absorption, transport, storage and catabolism. LXR activation enhances cholesterol efflux from lipid-laden macrophage-derived foam cells, which points to the potential utility of LXR agonists for the treatment of atherosclerosis. However, hepatic steatosis or hypertriglyceridemia due to LXR-mediated induction of SREBP-1c and fatty acid synthesis is a common obstacle to pharmaceutical development of LXR ligands. Here we describe the identification of a nonsteroidal ligand, WYE-672, that shows a cell-selective pattern of activity with little efficacy in liver cells (LXRα dominant) compared to macrophages. WYE-672 displays greater than 20-fold binding selectivity for LXRβ (IC50 = 50 nM) and poor coactivator recruitment by the LXRα isoform. WYE-672 activated a Gal4-LXRα fusion protein in HEK293 cells but not in Huh-7 hepatocytes, and did not activate a Gal4-LXRα fusion protein in either cell type. WYE-672 increased endogenous ABCA1, ABCG1, and SREBP-1c gene expression in human (THP-1) and murine (J774) macrophage cell lines, and stimulated apoA1-dependent cholesterol efflux from lipid-laden THP-1 foam cells. By contrast, WYE-672 produced significantly smaller inductions of ABCA1, ABCG1 or SREBP-1c gene expression in human (HepG2) or mouse (AML-12) hepatocyte cell lines, and did not stimulate lipid accumulation in HepG2 cells. Treatment of male LDLR−/− mice with WYE-672 for 7 days induced ABCA1 and ABCG1 expression in the spleen and duodenum without corresponding activation of liver LXR target gene expression or steatosis. WYE-672 reduced atherosclerotic lesion size in LDLR−/− fed a Western diet. WYE-672 is thus a novel LXR agonist with a tissue-selective activity profile that discriminates between macrophage and hepatic LXR to promote atherosclerotic lesion regression without triggering accompanying deleterious hepatic lipid effects.