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REV-ERB and ROR nuclear receptors as drug targets

Key Points

  • The nuclear receptors retinoic acid receptor-related orphan receptor-α (RORα), RORβ, RORγ, REV-ERBα and REV-ERBβ were originally identified as orphan receptors. RORα and RORβ constitutively activate transcription, whereas REV-ERBα and REV-ERBβ constitutively silence transcription.

  • RORα and RORγ are now known to bind to sterols, with certain oxysterols having a very high affinity for these receptors. REV-ERBs have been found to bind to haem.

  • REV-ERBs function as ligand-dependent (that is, haem-dependent) silencers of transcription. The role of the endogenous ligands for the RORs is less clear, as several sterols and oxysterols have been suggested to function as agonists or inverse agonists.

  • The RORs and REV-ERBs have substantially overlapping functions as they usually recognize similar DNA response elements. These receptors have important roles in many physiological functions, including development, circadian rhythm, metabolism and immune function.

  • Over the past several years, synthetic ligands have been designed that target RORs and REV-ERBs. Many of these have high potency and have been used to examine the utility of targeting RORs and REV-ERBs in animal models of human disease.

  • Synthetic REV-ERB agonists alter the circadian rhythm and have beneficial effects on the metabolic profile in obese mice. REV-ERB agonists increase oxidative metabolism in the skeletal muscle and improve exercise endurance in mice.

  • Synthetic inverse agonists of ROR (that either target RORγ alone or both RORα and RORγ) are effective in treating and preventing autoimmunity in mouse models. Additionally, they have beneficial effects on glucose and lipid metabolism.

  • The continued refinement and development of synthetic ligands that target these former orphan nuclear receptors may yield novel therapeutics to treat a range of diseases in the future.

Abstract

The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders.

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Figure 1: Structure of the RORs and REV-ERBs.
Figure 2: Molecular mechanism of action of the RORs and REV-ERBs.
Figure 3: Role of RORs and REV-ERBs in regulation of the mammalian clock.
Figure 4: Structures of REV-ERB and ROR demonstrate their capacity to bind to natural ligands.
Figure 5: Development of selective ROR ligands.
Figure 6: ROR inverse agonists alter TH cell development.
Figure 7: ROR and REV-ERB in the regulation of physiological processes.

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Acknowledgements

The work of T.P.B. is supported by US National Institutes of Health (NIH) grants MH093429 and MH092769.

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Glossary

DNA response element

A short sequence of DNA that is specifically recognized and bound by a particular transcription factor. DNA response elements are often found in the promoter regions of genes, and confer the responsiveness of a gene to regulation by a particular transcription factor.

E box

A particular DNA response element that is recognized by transcription factors belonging to the basic helix–loop–helix domain-containing family, such as circadian locomotor output cycles protein kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1).

Period (τ)

The time that elapses for one complete oscillation or cycle of a particular activity (for example, locomotor activity). Typically, the period for a circadian rhythm is almost 24 hours. In the absence of any extrinsic stimuli that act to 'entrain' the circadian rhythm (such as light), the period may differ; for example, mice typically have a period of slightly less than 24 hours in the absence of entrainment.

ROR response element

A particular DNA response element that is recognized by retinoic acid receptor-related orphan receptors (RORs) and REV-ERBs.

T helper 17 cells

(TH17 cells). A subset of TH cells that produce interleukin-17 (IL-17) and provide microbial immunity at mucosa and epithelial barriers. They have been implicated in the development of autoimmune disease.

T cell

A type of lymphocyte that has a crucial role in cellular immunity. T cells can be distinguished from other lymphocytes based on the expression of the T cell receptor on their plasma membrane.

Apo structure

A receptor structure that is free from a bound ligand.

Inverse agonists

Ligands that suppress the basal activity of a receptor.

Wheel running activity

A measure of locomotor activity as defined by rodents running on a wheel within a cage.

Phase shift

A discrete alteration in an oscillation in locomotor activity or other measurable physiological activity along the time axis within a circadian rhythm.

Area under the curve

(AUC). The area under the curve that is generated by plotting the concentration of a drug in plasma against time.

Melatonin

A hormone that is produced by the pineal gland in a circadian manner and is associated with entrainment of the circadian rhythm.

Fibroblast growth factor 21

(FGF21). A hormone that has several metabolic activities. FGF21 protects animals from diet-induced obesity and lowers blood glucose and lipid levels when administered to diabetic rodents.

TReg cells

A subset of T cells that produce interleukin-10 (IL-10) and transforming growth factor-β (TGFβ) and have an important role in immune tolerance.

TH1 cells

A subset of T helper (TH) cells that produces interferon-γ (IFNγ) and has an important role in cellular immunity.

TH2 cells

A subset of T helper (TH) cells that produces interleukin-4 (IL-4), IL-5 and IL-13, and has an important role in humoral immunity.

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Kojetin, D., Burris, T. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 13, 197–216 (2014). https://doi.org/10.1038/nrd4100

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