The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis

Abstract

Research efforts spanning the past two decades have established a clear link between nuclear receptor function, regulation of the circadian clock and lipid homeostasis. As such, this family of receptors represents an important area of research. Recent advances in the field have identified two nuclear receptor subfamilies, the REV-ERBs and the 'retinoic acid receptor-related orphan receptors' (RORs), as critical regulators of the circadian clock with significant roles in lipid homeostasis. In this review, the latest information garnered from cutting-edge research on these two nuclear receptor subfamilies will be discussed. Through direct targeting of the REV-ERBs and RORs with synthetic ligands, generation of novel tools aimed at characterizing their function in vivo have been developed, which may lead to novel therapeutics for the treatment of metabolic disorders.

Figure 1. Comparison of human retinoic acid receptor-related orphan receptors and REV-ERB nuclear hormone receptors

(A) The numbers indicate amino acid identity relative to RORα. RORα4, RORβ1 and RORγ1 are shown. (B) The numbers indicate amino acid identity relative to REV-ERBα. AF: Activation-function; DBD: DNA-binding domain; LBD: Ligand-binding domain; ROR: Retinoic acid receptor-related orphan receptor.

Figure 2. Model illustrating the regulation of a target gene by both retinoic acid receptor-related orphan receptors and REV-ERB

REV-ERB functions as a receptor for heme, which is required for its activity as a repressor. Several sterols have been suggested as ligands for the RORs. In this cartoon, sterols regulate the constitutive activity of the RORs. ROR: Retinoic acid receptor-related orphan receptor; RORE: ROR response element.

Figure 3. Examples of retinoic acid receptor-related orphan receptor ligands

(A) Endogenous ROR ligands that have been proposed. (B) Synthetic ROR ligands that have been identified. ROR: Retinoic acid receptor-related orphan receptor.

Figure 4. Crystal structures of retinoic acid receptor-related orphan receptor α with two proposed endogenous ligands within the ligand-binding pocket

Figure 5. Crystal structures of retinoic acid receptor-related orphan receptor β with three proposed ligands

Figure 6. Crystal structures of retinoic acid receptor-related orphan receptor γ with three proposed endogenous ligands within the ligand-binding pocket

Figure 7. Examples of REV-ERB ligands

(A) Heme, the identified endogenous ligand for REV-ERB. (B) Two recently characterized REV-ERB-specific synthetic ligands.

Figure 8. Crystal structures of REV-ERB ligand-binding domain

(A) Heme bound in the ligand-binding pocket of REV-ERBβ, (B) REV-ERBβ in the absence of a ligand. (C) NCoR bound to REV-ERBα in the absence of heme. NCoR: Nuclear receptor corepressor.