REV-ERB

REV-ERB is the collective name for a pair of sister nuclear receptors, alpha (NR1D1) and beta (NR1D2). Unusually for this superfamily, they lack the C-terminal helix 12, the element required to recruit coactivators, and so they can only act as repressors: with ligand bound, REV-ERB sits on ROR response elements and brings in the NCoR/HDAC3 complex. Their endogenous ligand is heme, turning them into direct sensors of the cell’s heme status.

The clock–metabolism link

In the central clock feedback loop, REV-ERB represses transcription of Bmal1 and counteracts the activating ROR receptors; the oscillation this creates sets the phase of clock-controlled genes further downstream. Because the same HDAC3 complex also lands on hepatic genes for fat synthesis and glucose production and on muscle genes for oxidation, REV-ERB ties the body clock to metabolism more directly than almost any other factor.

The term shows up in research-compound catalogues thanks to the synthetic agonists SR9011 and SR9009 (stenabolic). Accurate attribution matters: a study from 2019 found that SR9009 still has metabolic effects in cells completely lacking REV-ERB, so off-target activity now sits at the centre of the debate rather than in a footnote. Related metabolic research focuses on PPAR-delta.

Related terms and material

See also preclinical and AMPK. The shop groups these under metabolic and circadian research compounds; our articles introduce SR9009 and compare it with cardarine.