Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Genes & Development |
Volume | 26 |
Issue number | 7 |
Pages (from-to) | 657-67 |
Number of pages | 11 |
ISSN | 0890-9369 |
DOIs | |
Publication status | Published - 1 Apr 2012 |
- 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
Research areas
ID: 137667716