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Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function.

The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

Pubmed ID: 22474260


  • Bugge A
  • Feng D
  • Everett LJ
  • Briggs ER
  • Mullican SE
  • Wang F
  • Jager J
  • Lazar MA


Genes & development

Publication Data

April 1, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P01 DK49210
  • Agency: NIDDK NIH HHS, Id: P30 DK19525
  • Agency: NIDDK NIH HHS, Id: R01 DK045586
  • Agency: NIDDK NIH HHS, Id: R01 DK45586

Mesh Terms

  • Animals
  • Cells, Cultured
  • Circadian Rhythm
  • Gene Expression Regulation
  • Genome
  • Histone Deacetylases
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins