Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

The nuclear receptor REVERB alpha is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERB alpha in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERB alpha-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverba drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERB alpha does not repress lipogenesis under basal conditions. REVERB alpha control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverb alpha(-/-) mouse). Repressive action of REVERB alpha in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.