Nuclear receptor signaling in the control of cholesterol homeostasis: Have the orphans found a home?

Cholesterol is essential for all mammalian cells. Cellular cholesterol requirements are met through de novo synthesis and uptake of plasma lipoproteins, homeostatic responses that are transcriptionally regulated by the sterol regulatory element-binding proteins (SREBPs). To prevent cytotoxicity attributable to accumulation of excess cholesterol, liver X receptors (LXRs) and the farnesoid X receptor (FXR), together with other members of the nuclear receptor superfamily, promote the storage, transport, and catabolism of sterols and their metabolites. Members of this metabolic nuclear receptor family include receptors for oxysterols (LXRs), bile acids (CAR, FXR, and PXR), and fatty acids (PPARs). Through coordinated regulation of transcriptional programs, these nuclear receptors regulate key aspects of cellular and whole-body sterol homeostasis, including cholesterol absorption, lipoprotein synthesis and remodeling, lipoprotein uptake by peripheral tissues, reverse cholesterol transport, and bile acid synthesis and absorption. This review focuses on the nuclear receptors that are central to the lipid metabolic signaling cascades, communication between lipid metabolites and their receptors, and the role of nuclear receptors in orchestrating the complex transcriptional programs that govern cholesterol and bile acid metabolism.