Liver X receptors and atherosclerosis: it is not all cholesterol.

A critical event in the development of atherosclerosis is the recruitment of macrophages to the underlying epithelial layer of blood vessel walls and the uncontrolled uptake of oxi-dized/modified cholesterol. Continued accumulation of oxi-dized/modified cholesterol by macrophages and an associated inflammatory response leads to foam cell formation and the initiation of atherosclerosis. 1 Reversing the process of macro-phage cholesterol accumulation and inhibiting inflammation in the blood vessel wall have been held out as potential novel treatments for atherosclerosis; however, other than injectable forms of apolipoprotein A1, 2 no drugs that either enhance macrophage cholesterol efflux or inhibit inflammation have been validated in the clinic for the treatment of cardiovascular disease. The liver X receptors (LXRα and LXRβ), members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, are promising drug targets for treating atherosclerosis because they regulate cholesterol efflux from macrophages at the transcriptional level and exert anti-inflammatory activity. The efflux of cholesterol from macrophages to lipid-poor apolipoprotein A1 and high-density lipoprotein is mediated by the ATP-binding cassette transporters A1 and G1. 4 Both genes are directly regulated by LXRs, 3 and it is widely assumed that the atheroprotective effects of synthetic LXR agonists are caused by increased macrophage cholesterol efflux via the upregulation of these 2 genes. Indeed, bone marrow transplan-tation experiments indicate that LXR activity in macrophages is required for the atheroprotective action of LXR agonists. 5 A recent study by Zhang et al, 6 however, indicated that LXR agonists could be antiatherogenic without stimulating macro-phage cholesterol efflux, calling into question the contribution of cholesterol transport to LXR activity. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kappus et al 7 now add another nail to the coffin of the LXR-cholesterol efflux hypothesis. In this new work, the authors demonstrate that LXR agonist treatment in mice with hematopoietic-or macrophage-specific deletion of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 reduces atherosclerosis to a degree comparable with control mice, an effect independent of cholesterol efflux because macrophages lacking ABC transporters are unable to efflux cholesterol in an LXR-dependent manner. If not cholesterol efflux, what then is the mechanism of LXR agonist–dependent antiatherogenic activity? Like many nuclear receptors, LXRs also inhibit inflammation in an agonist-dependent manner by interfering with the activity of nuclear factor-κβ. 3 Kappus et al 7 demonstrate that the anti-inflammatory effects of LXR agonist treatment are preserved in Abca1 −/− /Abcg1 −/− macrophages in vitro …