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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Author(s).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.
Author(s): Morgan RA, Beck KR, Nixon M, Homer NZM, Crawford AA, Melchers D, Houtman R, Meijer OC, Stomby A, Anderson AJ, Upreti R, Stimson RH, Olsson T, Michoel T, Cohain A, Ruusalepp A, Schadt EE, Bjorkegren JLM, Andrew R, Kenyon CJ, Hadoke PWF, Odermatt A, Keen JA, Walker BR
Publication type: Article
Publication status: Published
Journal: Scientific Reports
Year: 2017
Volume: 7
Online publication date: 06/09/2017
Acceptance date: 08/08/2017
Date deposited: 21/12/2017
ISSN (electronic): 2045-2322
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41598-017-10410-1
DOI: 10.1038/s41598-017-10410-1
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