Rev-erbα, a Heme Sensor That Coordinates Metabolic and Circadian Pathways
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-erbα, 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-erbα–mediated gene repression. Thus, Rev-erbα serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology.
“Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology27-29.”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [29]
Rev-erbα−/− mice display increased adiposity and mild hyperglycemia, but without insulin resistance.
“Indeed, Rev-erbα−/− mice displayed increased adiposity and mild hyperglycemia, but without insulin resistance.”
From Circadian control of glucose metabolism (2014) · cites this paper as [27]
Rev-erbα directly regulates the expression of multiple gluconeogenic enzymes in liver, including glucose-6-phosphatase and phosphoenolpyruvate.
“Rev-erbα directly regulates the expression of multiple gluconeogenic enzymes in liver, including glucose-6-phosphatase and phosphoenolpyruvate [27].”
From Circadian control of glucose metabolism (2014) · cites this paper as [27]
Cites
Obesity and Metabolic Syndrome in Circadian <i>Clock</i> Mutant Mice
Turek, F. W., Joshu, C., Kohsaka, A., Lin, E., Ivanova, G., McDearmon, E., Laposky, A., Losee-Olson, S., Easton, A., Jensen, D. R., et al. (2005) · Science · doi:10.1126/science.1108750 · Cited by 2,485 · see citing works
Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock
Panda, S., Antoch, M. P., Miller, B. H., Su, A. I., Schook, A. C., Straume, M., Schultz, P. G., Kay, S. A., Takahashi, J. S., & Hogenesch, J. B. (2002) · Cell · doi:10.1016/s0092-8674(02)00722-5 · Cited by 2,272 · see citing works
Preitner, N., Damiola, F., Luis-Lopez-Molina, Zakany, J., Duboule, D., Albrecht, U., & Schibler, U. (2002) · Cell · doi:10.1016/s0092-8674(02)00825-5 · Cited by 2,198 · see citing works
Molecular analysis of mammalian circadian rhythms
Reppert, S. M., & Weaver, D. R. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.647 · Cited by 1,444 · see citing works
A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock
Sato, T. K., Panda, S., Miraglia, L. J., Reyes, T. M., Rudic, R. D., McNamara, P., Naik, K. A., FitzGerald, G. A., Kay, S. A., & Hogenesch, J. B. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.018 · Cited by 1,115 · see citing works
Rudic, R. D., McNamara, P., Curtis, A.-M., Boston, R. C., Panda, S., Hogenesch, J. B., & FitzGerald, G. A. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020377 · Cited by 1,059 · see citing works
Mammalian circadian biology: elucidating genome-wide levels of temporal organization
Lowrey, P. L., & Takahashi, J. S. (2004) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.5.061903.175925 · Cited by 976 · see citing works
Ponka, P. (1999) · The American Journal of the Medical Sciences · doi:10.1097/00000441-199910000-00004 · Cited by 652 · see citing works
Nuclear Receptor Rev-erbα Is a Critical Lithium-Sensitive Component of the Circadian Clock
Yin, L., Wang, J., Klein, P. S., & Lazar, M. A. (2006) · Science · doi:10.1126/science.1121613 · Cited by 556 · see citing works
Self-citationThe orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1
Akashi, M., & Takumi, T. (2005) · Nature Structural & Molecular Biology · doi:10.1038/nsmb925 · Cited by 493 · see citing works
NPAS2: A Gas-Responsive Transcription Factor
Dioum, E. M., Rutter, J. P., Tuckerman, J. R., Gonzalez, G., Gilles‐Gonzalez, M., & McKnight, S. L. (2002) · Science · doi:10.1126/science.1078456 · Cited by 432 · see citing works
The mammalian circadian timing system: from gene expression to physiology
Gachon, F., Nagoshi, E., Brown, S., Ripperger, J. A., & Schibler, U. (2004) · Chromosoma · doi:10.1007/s00412-004-0296-2 · Cited by 382 · see citing works
Nutritional Regulation of Hepatic Heme Biosynthesis and Porphyria through PGC-1α
Handschin, C., Lin, J. D., Rhee, J., Peyer, A., Chin, S., Wu, P., Meyer, U., & Spiegelman, B. M. (2005) · Cell · doi:10.1016/j.cell.2005.06.040 · Cited by 380 · see citing works
Genome-Wide Expression Analysis inDrosophilaReveals Genes Controlling Circadian Behavior
Ceriani, M. F., Hogenesch, J. B., Yanovsky, M. J., Panda, S., Straume, M., & Kay, S. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09305.2002 · Cited by 358 · see citing works
Reciprocal regulation of haem biosynthesis and the circadian clock in mammals
Kaasik, K., & Lee, C. C. (2004) · Nature · doi:10.1038/nature02724 · Cited by 341 · see citing works
Genome-wide Expression Analysis of Mouse Liver Reveals CLOCK-regulated Circadian Output Genes
Oishi, K., Miyazaki, K., Kadota, K., Kikuno, R. F., Nagase, T., Atsumi, G.-I., Ohkura, N., Azama, T., Mesaki, M., Yukimasa, S., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304564200 · Cited by 341 · see citing works
Tsiftsoglou, A. S., Tsamadou, A. I., & Papadopoulou, L. C. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.10.017 · Cited by 281 · see citing works
Yin, L., & Lazar, M. A. (2005) · Molecular Endocrinology · doi:10.1210/me.2005-0057 · Cited by 274 · see citing works
Self-citationProperties, Entrainment, and Physiological Functions of Mammalian Peripheral Oscillators
Stratmann, M., & Schibler, U. (2006) · Journal of Biological Rhythms · doi:10.1177/0748730406293889 · Cited by 268 · see citing works
The Drosophila Nuclear Receptor E75 Contains Heme and Is Gas Responsive
Reinking, J., Lam, M. M. S., Pardee, K., Sampson, H. M., Liu, S., Yang, P., Williams, S. P., White, W. L., Lajoie, G., Edwards, A. M., et al. (2005) · Cell · doi:10.1016/j.cell.2005.07.005 · Cited by 260 · see citing works
A sense of time: how molecular clocks organize metabolism
Kohsaka, A., & Bass, J. T. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.11.005 · Cited by 233 · see citing works
Heme, iron, and the mitochondrial decay of ageing.
Atamna, H. (2004) · Ageing Research Reviews · doi:10.1016/j.arr.2004.02.002 · Cited by 169 · see citing works
Disrupted fat absorption attenuates obesity induced by a high‐fat diet in <i>Clock</i> mutant mice
Oishi, K., Atsumi, G.-I., Sugiyama, S., Kodomari, I., Kasamatsu, M., Machida, K., & Ishida, N. (2006) · FEBS Letters · doi:10.1016/j.febslet.2005.11.063 · Cited by 166 · see citing works
Sassa, S., & Kappas, A. (1983) · Journal of Clinical Investigation · doi:10.1172/jci110809 · Cited by 145 · see citing works
Adelmant, G., Begue, A., Stéhelin, D., & Laudet, V. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.8.3553 · Cited by 119 · see citing works
Burgess, S. C., Leone, T. C., Wende, A. R., Croce, M. A., Chen, Z., Sherry, A. D., Malloy, C. R., & Finck, B. N. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600050200 · Cited by 111 · see citing works
Zhu, Y., Hon, T., Ye, W., & Li, Z. (2002) · PubMed · Cited by 69 · see citing works
Boehning, D. F., & Snyder, S. H. (2002) · Science · doi:10.1126/science.1080339 · Cited by 50 · see citing works
Drosophila Nuclear Receptor E75 Is a Thiolate Hemoprotein
de Rosny, E., de Groot, A., Jullian-Binard, C., et al. (2006) · Biochemistry · doi:10.1021/bi060537a · Cited by 43 · see citing works
Ripperger, J. A. (2006) · Chronobiology International · doi:10.1080/07420520500464411 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611 · see citing works
Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Guarente, L. P., & Sassone-Corsi, P. (2008) · Cell · doi:10.1016/j.cell.2008.07.002 · Cited by 1,427 · see citing works
Buxton, O. M., Cain, S. W., O’Connor, S. P., Porter, J. H., Duffy, J. F., Wang, W., Czeisler, C. A., & Shea, S. A. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003200 · Cited by 932 · see citing works
Bile acid signaling in metabolic disease and drug therapy
Li, T., & Chiang, J. Y. L. (2014) · Pharmacological Reviews · doi:10.1124/pr.113.008201 · Cited by 935 · see citing works
Green, C. B., Takahashi, J. S., & Bass, J. (2008) · Cell · doi:10.1016/j.cell.2008.08.022 · Cited by 902 · see citing works
Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA
Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., & Rastinejad, F. (2008) · Nature · doi:10.1038/nature07413 · Cited by 808 · see citing works
Crosstalk between metabolism and circadian clocks
Reinke, H., & Asher, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0096-9 · Cited by 598 · see citing works
Circadian Mechanisms in Medicine
Allada, R., & Bass, J. (2021) · New England Journal of Medicine · doi:10.1056/nejmra1802337 · Cited by 519 · see citing works
Simcox, J. A., & McClain, D. A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.007 · Cited by 545 · see citing works
Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate
Watson, P. J., Fairall, L., Santos, G. M., & Schwabe, J. W. R. (2012) · Nature · doi:10.1038/nature10728 · Cited by 505 · see citing works
Ligand and Target Discovery by Fragment-Based Screening in Human Cells
Parker, C. G., Galmozzi, A., Wang, Y., Correia, B. E., Sasaki, K., Joslyn, C. M., Kim, A. S., Cavallaro, C. L., Lawrence, R. M., Johnson, S. R., et al. (2017) · Cell · doi:10.1016/j.cell.2016.12.029 · Cited by 439 · see citing works
Glucocorticoid regulation of the circadian clock modulates glucose homeostasis
So, A. Y.-L., Bernal, T. U., Pillsbury, M. L., Yamamoto, K. R., & Feldman, B. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909733106 · Cited by 431 · see citing works
Macrophages and Iron Metabolism
Soares, M. P., & Hamza, I. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.016 · Cited by 401 · see citing works
Schmutz, I., Ripperger, J. A., Baeriswyl-Aebischer, S., & Albrecht, U. (2010) · Genes & Development · doi:10.1101/gad.564110 · Cited by 361 · see citing works
Repairing mitochondrial dysfunction in disease
Sorrentino, V., Menzies, K. J., & Auwerx, J. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104908 · Cited by 337 · see citing works
Circadian control of glucose metabolism
Kalsbeek, A., la Fleur, S., & Fliers, E. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.03.002 · Cited by 338 · see citing works
Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins
Rajagopal, A., Rao, A. U., Amigo, J., Tian, M., Upadhyay, S. K., Hall, C., Uhm, S., Mathew, M. K., Fleming, M. D., Paw, B. H., et al. (2008) · Nature · doi:10.1038/nature06934 · Cited by 316 · see citing works
Emerging roles of the corepressors NCoR1 and SMRT in homeostasis
Mottis, A., Mouchiroud, L., & Auwerx, J. (2013) · Genes & Development · doi:10.1101/gad.214023.113 · Cited by 297 · see citing works
Metabolic adaptation establishes disease tolerance to sepsis
Weis, S., Carlos, A. R., Moita, M. R., Singh, S., Blankenhaus, B., Cardoso, S., Larsen, R., Rebelo, S., Schäuble, S., Del Barrio, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.031 · Cited by 284 · see citing works
“Expression of G6PC1 mRNA (Figure 4G) was decreased in human hepatocytic HepG2 cells exposed to heme, as compared to vehicle-treated controls, which is consistent with previous findings (Yin et al., 2007).”
Bersten, D. C., Sullivan, A. E., Peet, D. J., & Whitelaw, M. L. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3621 · Cited by 267 · see citing works
Circadian Clocks and Metabolism
Marcheva, B., Ramsey, K. M., Peek, C. B., Affinati, A., Maury, E., & Bass, J. (2013) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-25950-0_6 · Cited by 282 · see citing works
Clocks, metabolism, and the epigenome
Feng, D., & Lazar, M. A. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.026 · Cited by 271 · see citing works
“Heme Heme is a ligand of REV-ERBa and REV-ERBb and enhances corepressor recruitment and transcriptional repression (Raghuram et al., 2007; Yin et al., 2007; Pardee et al., 2009; Phelan et al., 2010) (Figure 3).”
The circadian clock in cancer development and therapy
Fu, L., & Kettner, N. M. (2013) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-396971-2.00009-9 · Cited by 251 · see citing works
The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism
Delezie, J., Dumont, S., Dardente, H., Oudart, H., Gréchez‐Cassiau, A., Klosen, P., Teboul, M., Delaunay, F., Pévet, P., & Challet, E. (2012) · The FASEB Journal · doi:10.1096/fj.12-208751 · Cited by 252 · see citing works
Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals
Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.01.024 · Cited by 235 · see citing works
Regulation of metabolism: the circadian clock dictates the time
Sahar, S., & Sassone-Corsi, P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.10.005 · Cited by 222 · see citing works
Nutrients, Clock Genes, and Chrononutrition
Oike, H., Oishi, K., & Kobori, M. (2014) · Current Nutrition Reports · doi:10.1007/s13668-014-0082-6 · Cited by 198 · see citing works
Zhang, G., & Cai, D. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00196.2011 · Cited by 171 · see citing works
Circadian disruption and sleep disorders in neurodegeneration
Shen, Y., Lv, Q.-K., Xie, W.-Y., Gong, S.-Y., Zhuang, S., Liu, J.-Y., Mao, C.-J., & Liu, C.-F. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00340-6 · Cited by 171 · see citing works
Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery
Oberoi, J., Fairall, L., Watson, P. J., Yang, J.-C., Czimmerer, Z., Kampmann, T., Goult, B. T., Greenwood, J. A., Gooch, J. T., Kallenberger, B. C., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1983 · Cited by 165 · see citing works
The circadian coordination of cell biology
Chaix, A., Zarrinpar, A., & Panda, S. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201603076 · Cited by 159 · see citing works
Klf15 orchestrates circadian nitrogen homeostasis
Jeyaraj, D., Scheer, F. A. J. L., Ripperger, J. A., Haldar, S. M., Lu, Y., Prosdocimo, D. A., Eapen, S. J., Eapen, B. L., Cui, Y., Mahabeleshwar, G. H., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.020 · Cited by 154 · see citing works
ROR nuclear receptors: Structures, related diseases, and drug discovery
Zhang, Y., Luo, X.-Y., Wu, D.-H., & Xu, Y. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.120 · Cited by 151 · see citing works
The circadian clock and glucocorticoids – interactions across many time scales
Dickmeis, T., Weger, B. D., & Weger, M. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.05.012 · Cited by 144 · see citing works
The Multifaceted Role of Heme in Cancer
Fiorito, V., Chiabrando, D., Petrillo, S., Bertino, F., & Tolosano, E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01540 · Cited by 129 · see citing works
REV-ERBα Regulates TH17 Cell Development and Autoimmunity
Amir, M., Chaudhari, S., Wang, R., Campbell, S., Mosure, S. A., Chopp, L. B., Lu, Q., Shang, J., Pelletier, O. B., He, Y., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.101 · Cited by 117 · see citing works
Lipids around the Clock: Focus on Circadian Rhythms and Lipid Metabolism
Gnocchi, D., Pedrelli, M., Hurt-Camejo, E., & Parini, P. (2015) · Biology · doi:10.3390/biology4010104 · Cited by 115 · see citing works
Structural and functional insights into nuclear receptor signaling
Jin, L., & Li, Y. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.08.007 · Cited by 112 · see citing works
Discovery and Characterization of HemQ
Dailey, T. A., Boynton, T. O., Albetel, A.-N., Gerdes, S., Johnson, M. K., & Dailey, H. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.142604 · Cited by 77 · see citing works
Boynton, T. O., Daugherty, L. E., Dailey, T. A., & Dailey, H. A. (2009) · Biochemistry · doi:10.1021/bi900850y · Cited by 61 · see citing works
Metabolism as an integral cog in the mammalian circadian clockwork
Gamble, K. L., & Young, M. E. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.786672 · Cited by 18 · see citing works
- Authors
- Yin, L., Wu, N., Curtin, J. C., Qatanani, M., Szwergold, N. R., Reid, R. A., Waitt, G. M., Parks, D. J., Pearce, K. H., Wisely, G. B., & Lazar, M. A.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Lazar, Mitchell A.
- Venue
- Science
- Published
- 2007-12-14
- Volume
- 318
- Issue
- 5857
- Pages
- 1786-1789
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1975191711
- Cited by
- 707
- References
- 30
- Citations by year
- 2026: 22 · 2025: 24 · 2024: 18 · 2023: 22 · 2022: 48 · 2021: 35 · 2020: 35 · 2019: 37 · 2018: 34 · 2017: 43 · 2016: 28 · 2015: 38 · 2014: 46 · 2013: 48 · 2012: 54
- FWCI
- 18.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK045586)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- NR1D1, heme sensing, circadian clock, metabolic homeostasis, hepatic gluconeogenesis, glucose homeostasis, energy metabolism, nuclear receptor corepressor, gene repression
- MeSH terms
- Histone Deacetylase 3, Animals, Biological Clocks, Cell Line, Circadian Rhythm, DNA-Binding Proteins, Energy Metabolism, Gene Expression Regulation, Gluconeogenesis, Glucose, Glucose-6-Phosphatase, Heme, Hemin, Histone Deacetylases, Homeostasis, Humans, Male, Nuclear Proteins, Repressor Proteins, Receptors, Cytoplasmic and Nuclear, Cell Line, Tumor, Mice, Metabolic Networks and Pathways, Nuclear Receptor Subfamily 1, Group D, Member 1, Nuclear Receptor Co-Repressor 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
