Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Deficiency of ATP-Binding Cassette Transporter B6 in Megakaryocyte Progenitors Accelerates Atherosclerosis in Mice.
A. J. Murphy, V. Sarrazy, N. Wang, N. Bijl, S. Abramowicz, M. Westerterp, C. B. Welch, J. D. Schuetz, and L. Yvan-Charvet (2014)
Arterioscler Thromb Vasc Biol 34, 751-758
   Abstract »    Full Text »    PDF »
Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis.
V. Nin, C. C. S. Chini, C. Escande, V. Capellini, and E. N. Chini (2014)
J. Biol. Chem. 289, 5518-5527
   Abstract »    Full Text »    PDF »
Apolipoprotein A-IV Reduces Hepatic Gluconeogenesis through Nuclear Receptor NR1D1.
X. Li, M. Xu, F. Wang, A. B. Kohan, M. K. Haas, Q. Yang, D. Lou, S. Obici, W. S. Davidson, and P. Tso (2014)
J. Biol. Chem. 289, 2396-2404
   Abstract »    Full Text »    PDF »
The orphan nuclear receptors at their 25-year reunion.
S. E. Mullican, J. R. DiSpirito, and M. A. Lazar (2013)
J. Mol. Endocrinol. 51, T115-T140
   Abstract »    Full Text »    PDF »
Road to exercise mimetics: targeting nuclear receptors in skeletal muscle.
W. Fan, A. R. Atkins, R. T. Yu, M. Downes, and R. M. Evans (2013)
J. Mol. Endocrinol. 51, T87-T100
   Abstract »    Full Text »    PDF »
Understanding nuclear receptor form and function using structural biology.
F. Rastinejad, P. Huang, V. Chandra, and S. Khorasanizadeh (2013)
J. Mol. Endocrinol. 51, T1-T21
   Abstract »    Full Text »    PDF »
FLVCR is necessary for erythroid maturation, may contribute to platelet maturation, but is dispensable for normal hematopoietic stem cell function.
J. C. H. Byon, J. Chen, R. T. Doty, and J. L. Abkowitz (2013)
Blood 122, 2903-2910
   Abstract »    Full Text »    PDF »
Increased Atherosclerotic Lesions in LDL Receptor Deficient Mice With Hematopoietic Nuclear Receptor Rev-erb{alpha} Knock- Down.
H. Ma, W. Zhong, Y. Jiang, C. Fontaine, S. Li, J. Fu, V. M. Olkkonen, B. Staels, and D. Yan (2013)
JAHA 2, e000235
   Abstract »    Full Text »    PDF »
Association of Rev-erb{alpha} in adipose tissues with Type 2 diabetes mellitus amelioration after gastric bypass surgery in Goto-Kakizaki rats.
R. Zhang, C. Yan, X. Zhou, B. Qian, F. Li, Y. Sun, C. Shi, B. Li, S. Saito, K. Horimoto, et al. (2013)
Am J Physiol Regulatory Integrative Comp Physiol 305, R134-R146
   Abstract »    Full Text »    PDF »
Heme Sensor Proteins.
H. M. Girvan and A. W. Munro (2013)
J. Biol. Chem. 288, 13194-13203
   Abstract »    Full Text »    PDF »
Emerging roles of the corepressors NCoR1 and SMRT in homeostasis.
A. Mottis, L. Mouchiroud, and J. Auwerx (2013)
Genes & Dev. 27, 819-835
   Abstract »    Full Text »    PDF »
Nuclear Receptors and Their Selective Pharmacologic Modulators.
T. P. Burris, L. A. Solt, Y. Wang, C. Crumbley, S. Banerjee, K. Griffett, T. Lundasen, T. Hughes, and D. J. Kojetin (2013)
Pharmacol. Rev. 65, 710-778
   Abstract »    Full Text »    PDF »
Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein.
X. Tong, D. Zhang, K. Buelow, A. Guha, B. Arthurs, H. J. M. Brady, and L. Yin (2013)
J. Biol. Chem. 288, 5417-5425
   Abstract »    Full Text »    PDF »
Circadian clock adjustment to plant iron status depends on chloroplast and phytochrome function.
P. A. Salome, M. Oliva, D. Weigel, and U. Kramer (2013)
EMBO J. 32, 511-523
   Abstract »    Full Text »    PDF »
Reciprocal Interaction of the Circadian Clock with the Iron Homeostasis Network in Arabidopsis.
S. Hong, S. A. Kim, M. L. Guerinot, and C. R. McClung (2013)
Plant Physiology 161, 893-903
   Abstract »    Full Text »    PDF »
Metabolism and the Circadian Clock Converge.
K. Eckel-Mahan and P. Sassone-Corsi (2013)
Physiol Rev 93, 107-135
   Abstract »    Full Text »    PDF »
Small Molecule Modulation of Nuclear Receptor Conformational Dynamics: Implications for Function and Drug Discovery.
D. J. Kojetin and T. P. Burris (2013)
Mol. Pharmacol. 83, 1-8
   Abstract »    Full Text »    PDF »
Metabolic compensation of the Neurospora clock by a glucose-dependent feedback of the circadian repressor CSP1 on the core oscillator.
G. Sancar, C. Sancar, and M. Brunner (2012)
Genes & Dev. 26, 2435-2442
   Abstract »    Full Text »    PDF »
Identification of Small Molecule Activators of Cryptochrome.
T. Hirota, J. W. Lee, P. C. St. John, M. Sawa, K. Iwaisako, T. Noguchi, P. Y. Pongsawakul, T. Sonntag, D. K. Welsh, D. A. Brenner, et al. (2012)
Science 337, 1094-1097
   Abstract »    Full Text »    PDF »
The nuclear receptor REV-ERB{alpha} is required for the daily balance of carbohydrate and lipid metabolism.
J. Delezie, S. Dumont, H. Dardente, H. Oudart, A. Grechez-Cassiau, P. Klosen, M. Teboul, F. Delaunay, P. Pevet, and E. Challet (2012)
FASEB J 26, 3321-3335
   Abstract »    Full Text »    PDF »
Impairment of heme biosynthesis induces short circadian period in body temperature rhythms in mice.
R. Iwadate, Y. Satoh, Y. Watanabe, H. Kawai, N. Kudo, Y. Kawashima, T. Mashino, and A. Mitsumoto (2012)
Am J Physiol Regulatory Integrative Comp Physiol 303, R8-R18
   Abstract »    Full Text »    PDF »
PpsR, a Regulator of Heme and Bacteriochlorophyll Biosynthesis, Is a Heme-sensing Protein.
L. Yin, V. Dragnea, and C. E. Bauer (2012)
J. Biol. Chem. 287, 13850-13858
   Abstract »    Full Text »    PDF »
Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption.
O. M. Buxton, S. W. Cain, S. P. O'Connor, J. H. Porter, J. F. Duffy, W. Wang, C. A. Czeisler, and S. A. Shea (2012)
Science Translational Medicine 4, 129ra43
   Abstract »    Full Text »    PDF »
Rev-erb{alpha} and Rev-erb{beta} coordinately protect the circadian clock and normal metabolic function.
A. Bugge, D. Feng, L. J. Everett, E. R. Briggs, S. E. Mullican, F. Wang, J. Jager, and M. A. Lazar (2012)
Genes & Dev. 26, 657-667
   Abstract »    Full Text »    PDF »
Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment.
G. Zhang and D. Cai (2011)
Am J Physiol Endocrinol Metab 301, E1004-E1012
   Abstract »    Full Text »    PDF »
Circadian Control of Epigenetic Modifications Modulates Metabolism.
H. Duez and B. Staels (2011)
Circ. Res. 109, 353-355
   Full Text »    PDF »
Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75.
L. Caceres, A. S. Necakov, C. Schwartz, S. Kimber, I. J. H. Roberts, and H. M. Krause (2011)
Genes & Dev. 25, 1476-1485
   Abstract »    Full Text »    PDF »
The circadian oscillator gene GIGANTEA mediates a long-term response of the Arabidopsis thaliana circadian clock to sucrose.
N. Dalchau, S. J. Baek, H. M. Briggs, F. C. Robertson, A. N. Dodd, M. J. Gardner, M. A. Stancombe, M. J. Haydon, G.-B. Stan, J. M. Goncalves, et al. (2011)
PNAS 108, 5104-5109
   Abstract »    Full Text »    PDF »
Crise de Foie, Redux?.
D. D. Moore (2011)
Science 331, 1275-1276
   Abstract »    Full Text »    PDF »
Thiol-disulfide Redox Dependence of Heme Binding and Heme Ligand Switching in Nuclear Hormone Receptor Rev-erb{beta}.
N. Gupta and S. W. Ragsdale (2011)
J. Biol. Chem. 286, 4392-4403
   Abstract »    Full Text »    PDF »
Endogenous Ligands for Nuclear Receptors: Digging Deeper.
M. Schupp and M. A. Lazar (2010)
J. Biol. Chem. 285, 40409-40415
   Abstract »    Full Text »    PDF »
Genome-Wide Profiling of the Core Clock Protein BMAL1 Targets Reveals a Strict Relationship with Metabolism.
F. Hatanaka, C. Matsubara, J. Myung, T. Yoritaka, N. Kamimura, S. Tsutsumi, A. Kanai, Y. Suzuki, P. Sassone-Corsi, H. Aburatani, et al. (2010)
Mol. Cell. Biol. 30, 5636-5648
   Abstract »    Full Text »    PDF »
A Novel Heme-responsive Element Mediates Transcriptional Regulation in Caenorhabditis elegans.
J. Sinclair and I. Hamza (2010)
J. Biol. Chem. 285, 39536-39543
   Abstract »    Full Text »    PDF »
Hemin Binds to Human Cytoplasmic Arginyl-tRNA Synthetase and Inhibits Its Catalytic Activity.
F. Yang, X. Xia, H.-Y. Lei, and E.-D. Wang (2010)
J. Biol. Chem. 285, 39437-39446
   Abstract »    Full Text »    PDF »
Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding.
X. Tong, M. Muchnik, Z. Chen, M. Patel, N. Wu, S. Joshi, L. Rui, M. A. Lazar, and L. Yin (2010)
J. Biol. Chem. 285, 36401-36409
   Abstract »    Full Text »    PDF »
Characterization of the Core Mammalian Clock Component, NPAS2, as a REV-ERB{alpha}/ROR{alpha} Target Gene.
C. Crumbley, Y. Wang, D. J. Kojetin, and T. P. Burris (2010)
J. Biol. Chem. 285, 35386-35392
   Abstract »    Full Text »    PDF »
Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin.
Z. Yang, J. D. Philips, R. T. Doty, P. Giraudi, J. D. Ostrow, C. Tiribelli, A. Smith, and J. L. Abkowitz (2010)
J. Biol. Chem. 285, 28874-28882
   Abstract »    Full Text »    PDF »
T. A. Dailey, T. O. Boynton, A.-N. Albetel, S. Gerdes, M. K. Johnson, and H. A. Dailey (2010)
J. Biol. Chem. 285, 25978-25986
   Abstract »    Full Text »    PDF »
Nuclear Receptors Linking Circadian Rhythms and Cardiometabolic Control.
H. Duez and B. Staels (2010)
Arterioscler Thromb Vasc Biol 30, 1529-1534
   Abstract »    Full Text »    PDF »
E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb{alpha}.
L. Yin, S. Joshi, N. Wu, X. Tong, and M. A. Lazar (2010)
PNAS 107, 11614-11619
   Abstract »    Full Text »    PDF »
Dietary iron restriction or iron chelation protects from diabetes and loss of {beta}-cell function in the obese (ob/ob lep-/-) mouse.
R. C. Cooksey, D. Jones, S. Gabrielsen, J. Huang, J. A. Simcox, B. Luo, Y. Soesanto, H. Rienhoff, E. Dale Abel, and D. A. McClain (2010)
Am J Physiol Endocrinol Metab 298, E1236-E1243
   Abstract »    Full Text »    PDF »
Regulation of FGF21 Expression and Secretion by Retinoic Acid Receptor-related Orphan Receptor {alpha}.
Y. Wang, L. A. Solt, and T. P. Burris (2010)
J. Biol. Chem. 285, 15668-15673
   Abstract »    Full Text »    PDF »
Heme-responsive DNA Binding by the Global Iron Regulator Irr from Rhizobium leguminosarum.
C. Singleton, G. F. White, J. D. Todd, S. J. Marritt, M. R. Cheesman, A. W. B. Johnston, and N. E. Le Brun (2010)
J. Biol. Chem. 285, 16023-16031
   Abstract »    Full Text »    PDF »
Interaction of MAGED1 with nuclear receptors affects circadian clock function.
X. Wang, J. Tang, L. Xing, G. Shi, H. Ruan, X. Gu, Z. Liu, X. Wu, X. Gao, and Y. Xu (2010)
EMBO J. 29, 1389-1400
   Abstract »    Full Text »    PDF »
A wheel of time: the circadian clock, nuclear receptors, and physiology.
X. Yang (2010)
Genes & Dev. 24, 741-747
   Abstract »    Full Text »    PDF »
The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors.
I. Schmutz, J. A. Ripperger, S. Baeriswyl-Aebischer, and U. Albrecht (2010)
Genes & Dev. 24, 345-357
   Abstract »    Full Text »    PDF »
Modulation of Retinoic Acid Receptor-related Orphan Receptor {alpha} and {gamma} Activity by 7-Oxygenated Sterol Ligands.
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)
PNAS 106, 22510-22515
   Abstract »    Full Text »    PDF »
Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition.
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)
J Appl Physiol 107, 1972-1980
   Abstract »    Full Text »    PDF »
Molecular control of circadian metabolic rhythms.
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)
J Appl Physiol 107, 1965-1971
   Abstract »    Full Text »    PDF »
Clock genes and metabolic disease.
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 »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882