Recent studies have identified the liver X receptor-α (LXR-α) and LXR-β as important transcriptional regulators of cholesterol metabolism and transport. In Proceedings of the National Academy of Science, Tangirala et al. show that LXRs expressed by macrophages protect against atherosclerosis in mouse models of the disease.

LXRs were first identified in the liver, and they are members of the nuclear hormone receptor superfamily of transcription factors. They bind and are activated by cholesterol, whereupon they are involved in regulating the expression of genes involved in sterol absorption and transport, and several genes involved in cholesterol and fatty-acid metabolism. However, LXRs are also expressed in non-hepatic cells, and are involved in regulating the expression of ATP-binding cassette 1 (ABC1) and apolipoprotein E; proteins that have important functions in promoting the transfer of cholesterol to receptors, such as high-density lipoprotein (HDL), in a process known as reverse cholesterol transport. The importance of this process of reverse transport can be seen in the rare genetic condition Tangier disease, in which patients do not express ABC1. The patients have reduced HDL levels; they accumulate cholesterol in tissues and have an increased risk of atherosclerosis. As LXRs are expressed on macrophages — a cell type that is involved in the formation of atherosclerotic plaques — the authors sought to identify a direct link between LXR signalling from macrophages and the pathogenesis of cardiovascular disease.

To investigate the role of LXR expression on macrophages in atherosclerosis, macrophage-selective knockout mice were created. The use of selective knockouts is a useful technique to investigate a cell-specific contribution without interference of the loss of function in other tissues. Bone marrow from Lxr-deficient mice was transferred to lethally irradiated mouse models of atherosclerosis. The recipient mice showed selective loss of LXR activity in bone-marrow-derived cells, increased cholesterol accumulation and accelerated atherosclerosis. These results show a direct link between LXR activity and cardiovascular disease.

Although these results have yet to be achieved in other animal models and humans, LXR agonists might be useful drugs for the prevention of cardiovascular disease. Such agonists have been shown to reduce atherosclerosis in several mouse models of the disease. However, it is possible that such drugs would have to be delivered to macrophages or atherosclerotic sites directly, because the animals given LXR agonists have shown elevated serum triglycerides, probably as a result of fatty-acid synthesis in the liver.