Treatment of cells with oxysterols, natural LXR ligands derived from cholesterol, or synthetic LXR agonists promotes the effl ux of cholesterol by increasing expression of the ATP binding cassette transporters ABCA1 and ABCG1 and the apoli-

This article is available online at http://www.jlr.org early event in the development of atherosclerosis is the recruitment of macrophages to the subendothelial space of vessel walls and the uncontrolled uptake of oxidized or aggregated low density lipoprotein particles. Continued accumulation of oxidized or aggregated LDL by macrophages and an associated infl ammatory response leads to foam cell formation and the initiation of atherosclerosis ( 2 ). The liver X receptors LXR (NR1H3) and LXR (NR1H2), members of the nuclear hormone receptor superfamily of transcription factors, have been identifi ed as important regulators of cholesterol homeostasis in multiple cell types, including macrophages ( 3 ). Treatment of cells with oxysterols, natural LXR ligands derived from cholesterol, or synthetic LXR agonists promotes the effl ux of cholesterol by increasing expression of the ATP binding cassette transporters ABCA1 and ABCG1 and the apolipoprotein E (apoE) ( 4, 5 ). ABCA1, ABCG1, and apoE all participate in the transfer of intracellular and plasma membrane cholesterol to HDL, a process termed reverse cholesterol transport ( 6 ). Importantly, LXR agonists reduce atherosclerosis in animal models of cardiovascular disease, and upregulation of ABC transporters can be detected in the atherosclerotic lesions of treated animals ( 7, 8 ). The ability of LXRs to inhibit pro-infl ammatory pathways may also contribute to the anti-atherogenic activities of these receptors ( 9 ). Previous work from our laboratory has demonstrated that LXR function in hemaAbstract The liver X receptors LXR and LXR play critical roles in maintaining lipid homeostasis by functioning as transcription factors that regulate genetic networks controlling the transport, catabolism, and excretion of cholesterol. The studies described in this report examine the individual anti-atherogenic activity of LXR and LXR and determine the ability of each subtype to mediate the biological response to LXR agonists. Utilizing individual knockouts of LXR and LXR in the Ldlr / background, we demonstrate that LXR has a dominant role in limiting atherosclerosis in vivo. Functional studies in macrophages indicate that LXR is required for a robust response to LXR ligands, whereas LXR functions more strongly as a repressor. Furthermore, selective knockout of LXR in hematopoietic cells and rescue experiments indicate that the anti-atherogenic activity of this LXR subtype is not restricted to macrophages. These studies indicate that LXR plays a selective role in limiting atherosclerosis in response to hyperlipidemia. —Bischoff, E. D., C. L. Daige, M. Petrowski, H. Dedman, J. Pattison, J. Juliano, A. C. Li, and I. G. Schulman. Non-redundant roles for LXR and LXR in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J. Lipid Res . 2010. 51: 900–906.