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Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Lookup NU author(s): Professor Brian Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
BHF
Wellcome Trust

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