It also regulates several physiological processes under circadian control, including metabolic and immune pathways.

[6][8] Rev-Erbɑ was discovered in 1989 by Nobuyuki Miyajima and colleagues, who identified two erbA homologs on human chromosome 17 that were transcribed from opposite DNA strands in the same locus.

One of the genes encoded a protein that was highly similar to chicken thyroid hormone receptor, and the other, which they termed ear-1, would later be described as Rev-Erbɑ.

[12] The NR1D1 (nuclear receptor subfamily 1 group D member 1) gene, located on chromosome 17, encodes the protein REV-ERBɑ in humans.

[6] Rev-Erbα recruits the NCoR-HDAC3 complex through binding a specific DNA sequence commonly referred to as RORE due to its interaction with the transcriptional activator Retinoic Acid Receptor-related Orphan Receptor (ROR).

The primary TTFL features transcriptional activator proteins CLOCK and BMAL1 that contribute to the rhythmic expression of genes within this loop, notably per and cry.

The occupancy of the BMAL1 promoter by these two receptors is key for proper timing of the core clock machinery in mammals.

[27] Rev-Erbα relays circadian signals into metabolic and inflammatory regulatory responses and vice versa, although the precise mechanisms underlying this relationship are not entirely understood.

[21] Rev-erbα regulates the expression of liver apolipoproteins, sterol regulatory element binding protein, and the fatty acid elongase elovl3 through its repressional activity[28][29][30] In addition, the silencing of Rev-erbα is associated with the reduction of fatty acid synthase, a key regulator of lipogenesis.

Researchers have proposed that Rev-erbα's role in adipocyte function may affect the timing of processes such as lipid storage and lipolysis, contributing to long term issues with BMI control.

[33] More directly, Rev-erbα's expression in the pancreas regulates the function of α-cells and β-cells, which produce glucagon and insulin, respectively.

[35] One study found that in patients with osteoarthritis has reduced Rev-erbα levels compared to normal cartilage.

[28][34] In the brain, Rev-erbα deletion causes a disruption in the oscillation of microglial activation and increases the expression of pro-inflammatory transcripts.

[40] In addition, Rev-erbα has been proposed to play a role in the regulation of midbrain dopamine production and mood-related behavior in mice through repression of tyrosine hydroxylase gene transcription.

[41] Rev-erbα has been proposed as a target in the treatment of bipolar disorder through lithium, which indirectly regulates the protein at a post-translational level.

Lithium inhibits glycogen synthase kinase (GSK 3β), an enzyme that phosphorylates and stabilizes Rev-erbα.