Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.
The circadian clock temporally coordinates metabolic homeostasis in mammals. Central to this is heme, an iron-containing porphyrin that serves as prosthetic group for enzymes involved in oxidative metabolism as well as transcription factors that regulate circadian rhythmicity. The circadian factor that integrates this dual function of heme is not known. We show that heme binds reversibly to the orphan nuclear receptor Rev-erbalpha, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erbalpha-mediated gene repression. Thus, Rev-erbalpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.
Yin
Lei
L
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Wu
Nan
N
Curtin
Joshua C
JC
Qatanani
Mohammed
M
Szwergold
Nava R
NR
Reid
Robert A
RA
Waitt
Gregory M
GM
Parks
Derek J
DJ
Pearce
Kenneth H
KH
Wisely
G Bruce
GB
Lazar
Mitchell A
MA
D000818:Animals; D001683:Biological Clocks; D002460:Cell Line; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000099186:Histone Deacetylase 3
D004268:DNA-Binding Proteins; D005947:Glucose; D005952:Glucose-6-Phosphatase; D006418:Heme; D006427:Hemin; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C064353:NR1D1 protein, human; C539128:Ncor1 protein, mouse; C498262:Nr1d1 protein, mouse