Lesion Macrophages Are a Key Target for the Antiatherogenic Effects of LXR Agonists
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The Liver X Receptors (LXRα and LXRβ) are members of the nuclear hormone receptor superfamily.1 These sterol-responsive transcription factors regulate the expression of a number of genes involved in intestinal cholesterol absorption, conversion of cholesterol to bile acids, and reverse cholesterol transport. Activation of LXRs blocks cholesterol absorption and induces cholesterol efflux from lipid-loaded cells such as macrophages. Because increased cholesterol efflux is predicted to limit the transformation of macrophages into atherosclerotic foam cells, LXR activity is predicted to be antiatherogenic. This hypothesis is supported by several studies using mice genetically deficient in LXR expression. Previous work from Tangirala and colleagues established that selective elimination of macrophage LXRα and LXRβ expression in the bone marrow compartment results in accelerated disease in both the spontaneous (ApoE−/−) and Western-diet inducible (LDLR−/−) models of atherosclerosis.2 Furthermore, LXRαβ double knockout mice fed a normal chow diet exhibit increased cholesterol accumulation in the macrophages of their arterial walls.2,3 In addition to their effects on cholesterol metabolism, activation of the LXRs by synthetic agonists has an inhibitory effect on inflammatory gene expression in macrophages, pointing to a second potential antiatherogenic mechanism of these receptors.4 Finally, recent studies suggest that the ability of microbial infections to modify the development of atherosclerosis may be accomplished in part through interference with the LXR signaling pathway and macrophage cholesterol metabolism.5
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Collectively, these studies point to LXRs as potential therapeutic targets for the treatment or prevention of atherosclerosis. However, it …