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Science 318 (5857): 1786-1789

Copyright © 2007 by the American Association for the Advancement of Science

Rev-erb{alpha}, a Heme Sensor That Coordinates Metabolic and Circadian Pathways

Lei Yin,1 Nan Wu,1 Joshua C. Curtin,1 Mohammed Qatanani,1 Nava R. Szwergold,1 Robert A. Reid,2 Gregory M. Waitt,2 Derek J. Parks,3 Kenneth H. Pearce,3 G. Bruce Wisely,3 Mitchell A. Lazar1*

Abstract: 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-erb{alpha}, 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-erb{alpha}–mediated gene repression. Thus, Rev-erb{alpha} serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.

1 Division of Endocrinology, Diabetes, and Metabolism; Department of Medicine; and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2 Department of Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709–3398, USA.
3 Department of Biological Reagents and Assay Development, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709–3398, USA.

* To whom correspondence should be addressed. E-mail: lazar{at}mail.med.upenn.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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X. Yang (2010)
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   Abstract »    Full Text »    PDF »
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I. Schmutz, J. A. Ripperger, S. Baeriswyl-Aebischer, and U. Albrecht (2010)
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   Abstract »    Full Text »    PDF »
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Y. Wang, N. Kumar, L. A. Solt, T. I. Richardson, L. M. Helvering, C. Crumbley, R. D. Garcia-Ordonez, K. R. Stayrook, X. Zhang, S. Novick, et al. (2010)
J. Biol. Chem. 285, 5013-5025
   Abstract »    Full Text »    PDF »
PGC-1{alpha} negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb{alpha} axis.
J. L. Estall, J. L. Ruas, C. S. Choi, D. Laznik, M. Badman, E. Maratos-Flier, G. I. Shulman, and B. M. Spiegelman (2009)
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   Abstract »    Full Text »    PDF »
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P. La, A. P. Fernando, Z. Wang, A. Salahudeen, G. Yang, Q. Lin, C. J. Wright, and P. A. Dennery (2009)
J. Biol. Chem. 284, 36302-36311
   Abstract »    Full Text »    PDF »
Rev-erb-{alpha}: an integrator of circadian rhythms and metabolism.
H. Duez and B. Staels (2009)
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   Abstract »    Full Text »    PDF »
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S. Li and J. D. Lin (2009)
J Appl Physiol 107, 1959-1964
   Abstract »    Full Text »    PDF »
How nuclear receptors tell time.
M. Teboul, A. Grechez-Cassiau, F. Guillaumond, and F. Delaunay (2009)
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   Abstract »    Full Text »    PDF »
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B. Marcheva, K. M. Ramsey, A. Affinati, and J. Bass (2009)
J Appl Physiol 107, 1638-1646
   Abstract »    Full Text »    PDF »
Fat circadian biology.
J. M. Gimble and Z. E. Floyd (2009)
J Appl Physiol 107, 1629-1637
   Abstract »    Full Text »    PDF »
Glucocorticoid regulation of the circadian clock modulates glucose homeostasis.
A. Y.-L. So, T. U. Bernal, M. L. Pillsbury, K. R. Yamamoto, and B. J. Feldman (2009)
PNAS 106, 17582-17587
   Abstract »    Full Text »    PDF »
Bile acids: regulation of synthesis.
J. Y. L. Chiang (2009)
J. Lipid Res. 50, 1955-1966
   Abstract »    Full Text »    PDF »
Negative feedback maintenance of heme homeostasis by its receptor, Rev-erb{alpha}.
N. Wu, L. Yin, E. A. Hanniman, S. Joshi, and M. A. Lazar (2009)
Genes & Dev. 23, 2201-2209
   Abstract »    Full Text »    PDF »
Evidence of carbon monoxide-mediated phase advancement of the yeast metabolic cycle.
B. P. Tu and S. L. McKnight (2009)
PNAS 106, 14293-14296
   Abstract »    Full Text »    PDF »
Nuclear receptor-like transcription factors in fungi.
A. M. Naar and J. K. Thakur (2009)
Genes & Dev. 23, 419-432
   Abstract »    Full Text »    PDF »
The Circadian Clock in Arabidopsis Roots Is a Simplified Slave Version of the Clock in Shoots.
A. B. James, J. A. Monreal, G. A. Nimmo, C. L. Kelly, P. Herzyk, G. I. Jenkins, and H. G. Nimmo (2008)
Science 322, 1832-1835
   Abstract »    Full Text »    PDF »
Ligand modulation of REV-ERB{alpha} function resets the peripheral circadian clock in a phasic manner.
Q. J. Meng, A. McMaster, S. Beesley, W. Q. Lu, J. Gibbs, D. Parks, J. Collins, S. Farrow, R. Donn, D. Ray, et al. (2008)
J. Cell Sci. 121, 3629-3635
   Abstract »    Full Text »    PDF »
A Novel Heme-Regulatory Motif Mediates Heme-Dependent Degradation of the Circadian Factor Period 2.
J. Yang, K. D. Kim, A. Lucas, K. E. Drahos, C. S. Santos, S. P. Mury, D. G. S. Capelluto, and C. V. Finkielstein (2008)
Mol. Cell. Biol. 28, 4697-4711
   Abstract »    Full Text »    PDF »
Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity.
S. Sookoian, C. Gemma, T. F. Gianotti, A. Burgueno, G. Castano, and C. J. Pirola (2008)
Am J Clin Nutr 87, 1606-1615
   Abstract »    Full Text »    PDF »
CIRCADIAN RHYTHMS: Daily Watch on Metabolism.
T. Imaizumi, S. A. Kay, and J. I. Schroeder (2007)
Science 318, 1730-1731
   Abstract »    Full Text »    PDF »

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