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

Genes & development | Apr 1, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22474260

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 RIS Download

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

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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

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