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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author 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 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,
Project Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation
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Original article (peer-reviewed)

Journal Scientific Reports
Volume (Issue) 7
Page(s) 10633
Title of proceedings Scientific Reports
DOI 10.1038/s41598-017-10410-1

Open Access

URL https://www.nature.com/articles/s41598-017-10410-1
Type of Open Access Publisher (Gold Open Access)

Abstract

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.
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