The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs are activated in response to elevated cellular cholesterol levels, allowing them to function as "cholesterol sensors." Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. They also inhibit cholesterol uptake by inducing the expression of Idol, an E3 ubiquitin ligase that catalyzes the ubiquitination and degradation of the low-density lipoprotein (LDL) receptor. Synthetic LXR agonists promote cholesterol efflux in vivo and inhibit the development of atherosclerosis in animal models. Conversely, loss of LXR expression in mice leads to pathologic lipid accumulation and accelerated atherosclerosis. The ability of LXRs to coordinate cellular and systemic sterol homeostasis makes them potentially attractive targets for intervention in human metabolic disease.
