Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
Open accessAbstract
Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20β-dihydrocortisol (20β-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20β-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20β-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The human enzyme(s) responsible for formation of the 20β-hydroxy isomers of the cortols and cortolones has not yet been identified.
“the human enzyme(s) responsible for the formation of the 20β-hydroxy isomers of the cortols and cortolones has not yet been identified.”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [255]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen
Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0897 · Cited by 6,763 · see citing works
Wolber, G., & Langer, T. (2004) · Journal of Chemical Information and Modeling · doi:10.1021/ci049885e · Cited by 1,989 · see citing works
Edwards, C. R. W., Burt, D., McIntyre, M., de Kloet, E. R., Stewart, P. M., Brett, L., Sutanto, W. S., & Monder, C. (1988) · The Lancet · doi:10.1016/s0140-6736(88)90742-8 · Cited by 1,067 · see citing works
Mendelian randomization as an instrumental variable approach to causal inference
Didelez, V., & Sheehan, N. (2007) · Statistical Methods in Medical Research · doi:10.1177/0962280206077743 · Cited by 923 · see citing works
Seckl, J. R., & Walker, B. R. (2001) · Endocrinology · doi:10.1210/endo.142.4.8114 · Cited by 714 · see citing works
Self-citationBody condition scoring and weight estimation of horses
CARROLL, C. L., & Huntington, P. J. (1988) · Equine Veterinary Journal · doi:10.1111/j.2042-3306.1988.tb01451.x · Cited by 623 · see citing works
Hayek, T., Fuhrman, B., Vaya, J., Rosenblat, M., Belinky, P. A., Coleman, R., Elis, A., & Aviram, M. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.11.2744 · Cited by 552 · see citing works
Obesity and Gender Influence Cortisol Secretion and Metabolism in Man
Andrew, R., Phillips, D. I. W., & Walker, B. R. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.5.4951 · Cited by 351 · see citing works
Self-citationWermuth, B. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)69950-3 · Cited by 320 · see citing works
Profiling steroid hormones and urinary steroids
Shackleton, C. H. L. (1986) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)80683-0 · Cited by 291 · see citing works
Franzén, O., Ermel, R., Cohain, A., Akers, N. K., Di Narzo, A., Talukdar, H. A., Foroughi-Asl, H., Giambartolomei, C., Fullard, J. F., Sukhavasi, K., et al. (2016) · Science · doi:10.1126/science.aad6970 · Cited by 288 · see citing works
Self-citationFactors affecting the circadian rhythm in plasma cortisol concentrations in the horse
IRVINE, C. H. G., & Alexander, S. L. (1994) · Domestic Animal Endocrinology · doi:10.1016/0739-7240(94)90030-2 · Cited by 253 · see citing works
Disentangling molecular relationships with a causal inference test
Millstein, J., Zhang, B., Zhu, J. W., & Schadt, E. E. (2009) · BMC Genetics · doi:10.1186/1471-2156-10-23 · Cited by 230 · see citing works
Self-citationAn Unbiased Cell Morphology–Based Screen for New, Biologically Active Small Molecules
Tanaka, M., Bateman, R. L., Rauh, D., Vaisberg, E. A., Ramachandani, S., Zhang, C., Hansen, K. C., Burlingame, A. L., Trautman, J. K., Shokat, K. M., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030128 · Cited by 229 · see citing works
Oppermann, U. C. T. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105316 · Cited by 222 · see citing works
Forrest, G. L., & Gonzalez, B. (2000) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(00)00196-4 · Cited by 210 · see citing works
Prevalence of obesity in riding horses in Scotland
Wyse, C. A., McNie, K. A., Tannahil, V. J., Love, S., & Murray, J. (2008) · Veterinary Record · doi:10.1136/vr.162.18.590 · Cited by 200 · see citing works
Olson, L. E., Bedja, D., Alvey, S. J., Cardounel, A. J., Gabrielson, K. L., & Reeves, R. H. (2003) · PubMed · Cited by 165 · see citing works
Hemani, G., Zheng, J., Wade, K. H., Laurin, C., Elsworth, B., Burgess, S., Bowden, J., Langdon, R., Tan, V. Y., Yarmolinsky, J., et al. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/078972 · Cited by 133 · see citing works
Burgess, S. (2018) · Apollo (University of Cambridge) · doi:10.17863/cam.26250 · Cited by 118 · see citing works
Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol
Strain, G. W., Zumoff, B., Kream, J., Strain, J. J., Levin, J., & Fukushima, D. K. (1982) · Metabolism · doi:10.1016/0026-0495(82)90054-3 · Cited by 114 · see citing works
11β-Hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome
Wake, D. J., & Walker, B. R. (2004) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2003.11.015 · Cited by 111 · see citing works
Self-citation5α-Reductase Type 1 Modulates Insulin Sensitivity in Men
Upreti, R., Hughes, K. A., Livingstone, D. E. W., Gray, C. D., Minns, F. C., Macfarlane, D. P., Marshall, I., Stewart, L. H., Walker, B. R., & Andrew, R. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1395 · Cited by 88 · see citing works
Self-citationDowman, J. K., Hopkins, L., Reynolds, G. M., Armstrong, M. J., Nasiri, M., Nikolaou, N., van Houten, E. L. A. F., Visser, J. A., Morgan, S., Lavery, G. G., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1592 · Cited by 82 · see citing works
Hughes, K. A., Webster, S., & Walker, B. (2008) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.17.4.481 · Cited by 77 · see citing works
Self-citationTHE METABOLISM OF CORTISOL BY HUMAN EXTRA-HEPATIC TISSUES
Jenkins, J. S. (1966) · Journal of Endocrinology · doi:10.1677/joe.0.0340051 · Cited by 73 · see citing works
Immunohistochemical localization of carbonyl reductase in human tissues.
Wirth, H., & Wermuth, B. (1992) · Journal of Histochemistry & Cytochemistry · doi:10.1177/40.12.1453004 · Cited by 73 · see citing works
Malátková, P., Maser, E., & Wsól, V. (2010) · Current Drug Metabolism · doi:10.2174/138920010794233530 · Cited by 73 · see citing works
Rashid, M. A., Lee, S., Tak, E., Lee, J., Choi, T. G., Lee, J.-W., Kim, J. B., Youn, J. H., Kang, I., Ha, J., et al. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.08.015 · Cited by 55 · see citing works
Atucha, E., Zalachoras, I., van den Heuvel, J. K., van Weert, L. T. C. M., Melchers, D., Mol, I. M., Belanoff, J. K., Houtman, R., Hunt, H., Roozendaal, B., et al. (2015) · Endocrinology · doi:10.1210/en.2015-1390 · Cited by 54 · see citing works
Self-citation5α-Reduced Glucocorticoids, Novel Endogenous Activators of the Glucocorticoid Receptor
McInnes, K. J., Kenyon, C. J., Chapman, K. E., Livingstone, D. E. W., Macdonald, L. J., Walker, B. R., & Andrew, R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402822200 · Cited by 52 · see citing works
Self-citationThe metabolism of cortisol and progesterone by cultured uterine fibroblasts, strain U12-705
Sweat, M. L., GROSSER, B. I., Berliner, D. L., et al. (1958) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(58)90524-9 · Cited by 50 · see citing works
Abel, S. M., Maggs, J. L., Back, D. J., & Park, B. K. (1992) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(92)90297-v · Cited by 47 · see citing works
Flavonoids as inhibitors of human carbonyl reductase 1
Carlquist, M., Frejd, T., & Gorwa‐Grauslund, M. F. (2008) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2008.05.021 · Cited by 39 · see citing works
Lakhman, S. S., Chen, X., González-Covarrubias, V., et al. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.035550 · Cited by 39 · see citing works
Jo, A., Choi, T. G., Jo, Y. H., et al. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6457 · Cited by 37 · see citing works
Regulation of human carbonyl reductase 1 (CBR1, SDR21C1) gene by transcription factor Nrf2
Miura, T., Taketomi, A., Nishinaka, T., & Terada, T. (2012) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2012.11.023 · Cited by 36 · see citing works
Kornel, L., Miyabo, S., SAITO, Z., CHA, R.-W., & WU, F.-T. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-40-6-949 · Cited by 35 · see citing works
Guo, C., Wang, W., Liu, C., Myatt, L., & Sun, K. (2014) · Endocrinology · doi:10.1210/en.2013-1848 · Cited by 32 · see citing works
Metabolism of cortisol-4-C14 in patients with infectious and collagen diseases
Ichikawa, Y. (1966) · Metabolism · doi:10.1016/0026-0495(66)90123-5 · Cited by 31 · see citing works
The modulation of carbonyl reductase 1 by polyphenols
Boušová, I., Skálová, L., Souček, P., & Matoušková, P. (2015) · Drug Metabolism Reviews · doi:10.3109/03602532.2015.1089885 · Cited by 27 · see citing works
Kalabus, J. L., Cheng, Q., Jamil, R. G., Schuetz, E. G., & Blanco, J. G. (2012) · Toxicology Letters · doi:10.1016/j.toxlet.2012.04.006 · Cited by 27 · see citing works
Cortisol metabolism in vitro—II. Species difference
Abel, S. M., Back, D. J., Maggs, J. L., & Park, B. K. (1993) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(93)90013-m · Cited by 24 · see citing works
Cofactor Profiling of the Glucocorticoid Receptor from a Cellular Environment
Desmet, S. J., Dejager, L., Clarisse, D., et al. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1346-6_8 · Cited by 23 · see citing works
Beck, K. R., Sommer, T. J., Schuster, D., & Odermatt, A. (2016) · Toxicology · doi:10.1016/j.tox.2016.09.014 · Cited by 22 · see citing works
Self-citationQuiñones‐Lombraña, A., Ferguson, D. C. J., Blair, R. H., Kalabus, J. L., Redzematovic, A., & Blanco, J. G. (2014) · Pharmaceutical Research · doi:10.1007/s11095-013-1267-1 · Cited by 21 · see citing works
Covarrubias, V. G., Lakhman, S. S., Forrest, A., et al. (2006) · Toxicology Letters · doi:10.1016/j.toxlet.2006.01.004 · Cited by 19 · see citing works
Schelcher, F., Picard‐Hagen, N., Laroute, V., et al. (1999) · Endocrinology · doi:10.1210/endo.140.5.6896 · Cited by 19 · see citing works
Schöneshöfer, M., Weber, B., & Nigám, S. K. (1983) · Clinical Chemistry · doi:10.1093/clinchem/29.2.385 · Cited by 19 · see citing works
Ebert, B., Kisiela, M., & Maser, E. (2016) · Drug Metabolism Reviews · doi:10.3109/03602532.2016.1167902 · Cited by 14 · see citing works
Metabolism of Reichstein's Substance E in Man
Bradlow, H. L., Fukushima, D. K., Zumoff, B., et al. (1962) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-22-7-748 · Cited by 12 · see citing works
Voice, M. W., Seckl, J. R., & Chapman, K. E. (1996) · Gene · doi:10.1016/s0378-1119(96)00490-8 · Cited by 10 · see citing works
New approaches to detect cortisol administration in the horse
Popot, M. A., LACABARATZ, E., Garcia, P., et al. (1999) · Equine Veterinary Journal · doi:10.1111/j.2042-3306.1999.tb03817.x · Cited by 9 · see citing works
Discriminant value of blood and urinary corticoids for the diagnosis of scrapie in live sheep
Picard‐Hagen, N., Gayrard, V., Laroute, V., et al. (2002) · Veterinary Record · doi:10.1136/vr.150.22.680 · Cited by 6 · see citing works
Biotransformations of the C-20-Dihydro Metabolites of Cortisol in Man
Bradlow, H. L., Zumoff, B., Fukushima, D. K., et al. (1972) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-34-6-997 · Cited by 5 · see citing works
In vitro metabolism studies of [1,2,6,7-3H]-cortisol in human gingiva in health and disease
ElAttar, T. M. A. (1975) · Steroids · doi:10.1016/0039-128x(75)90092-6 · Cited by 4 · see citing works
Metabolism of cortisol by human thrombocytes
Arie, R., Hoogervorst-Spalter, H., Kaufmann, H., et al. (1979) · Metabolism · doi:10.1016/0026-0495(79)90170-7 · Cited by 3 · see citing works
Rashid, M. A., Lee, S., Tak, E., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.07.011 · Cited by 2 · see citing works
Kemény, V., Farkas, K., & Gömör, B. (1970) · PubMed · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
“reductase 1 has been described a relevant 20-HSD for cortisol in humans [255], the”
- Authors
- Morgan, R. A., Beck, K. R., Nixon, M., Homer, N. Z. M., Crawford, A. A., Melchers, D., Houtman, R., Meijer, O. C., Stomby, A., Anderson, A. J., Upreti, R., Stimson, R. H., Olsson, T., Michoel, T., Cohain, A., Ruusalepp, A., Schadt, E. E., Björkegren, J. L. M., Andrew, R., Kenyon, C. J., Hadoke, P. W. F., Odermatt, A., Keen, J. A., & Walker, B. R.
- Affiliations
- The Queen's Medical Research Institute (GB)
- University of Basel (CH)
- University of Bristol (GB)
- PamGene (Netherlands) (NL)
- Leiden University Medical Center (NL)
- Umeå University (SE)
- Roslin Institute (GB)
- Icahn School of Medicine at Mount Sinai (US)
- Tartu University Hospital (EE)
- University of Edinburgh (GB)
- Corresponding author
- Morgan, Ruth A.
- ORCID
- Morgan, Ruth A.
- Beck, Katharina R.
- Nixon, Mark
- Homer, Natalie Z. M.
- Crawford, Andrew A.
- Melchers, Diana
- Houtman, René
- Meijer, Onno C.
- Stomby, Andreas
- Upreti, Rita
- Stimson, Roland H.
- Olsson, Tommy
- Michoel, Tom
- Cohain, Ariella
- Ruusalepp, Arno
- Schadt, Eric E.
- Björkegren, Johan L. M.
- Andrew, Ruth
- Hadoke, Patrick W. F.
- Odermatt, Alex
- Keen, John A.
- Walker, Brian R.
- Venue
- Scientific Reports
- Published
- 2017-09-06
- Volume
- 7
- Issue
- 1
- Pages
- 10633-10633
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5587574
- OpenAlex
- W2751393809
- Cited by
- 31
- References
- 59
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 6 · 2021: 3 · 2020: 1 · 2019: 5 · 2018: 3
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Explore Bristol Research (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Science Foundation
- Wellcome Trust (206587/Z/17/Z)
- Zoetis
- British Heart Foundation (RG/11/4/28734)
- University of Edinburgh
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31001, 159454)
- Universität Wien
- Universität Innsbruck
- Medical Research Council (MR/K010271/1)
- Biotechnology and Biological Sciences Research Council (1151241)
- National Heart, Lung, and Blood Institute (R01HL125863)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- carbonyl reductase 1, glucocorticoid metabolism, cortisol reduction, obesity, impaired glucose tolerance, diet-induced obesity, adipose tissue, horses, NADPH-dependent reduction
- MeSH terms
- Carbonyl Reductase (NADPH), Animals, Disease Models, Animal, Energy Metabolism, Female, Glucocorticoids, Horses, Humans, Hydrocortisone, Hydroxycorticosteroids, Liver, Male, Models, Molecular, Molecular Conformation, Obesity, Phenotype, Protein Binding, Receptors, Glucocorticoid, Structure-Activity Relationship, Genetic Variation, Gene Expression, Mice, Genetic Association Studies
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
