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

Research output: Contribution to journalArticle

  • Katharina R Beck
  • Diana Melchers
  • René Houtman
  • Onno C Meijer
  • Andreas Stomby
  • Anna J Anderson
  • Rita Upreti
  • Tommy Olsson
  • Ariella Cohain
  • Arno Ruusalepp
  • Eric E Schadt
  • Johan L M Björkegren
  • Alex Odermatt

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  • Morgan et al_CBR1_revised_clean document

    Rights statement: This is the Authors Accepted Manuscript as accepted by Nature Scientific Reports on 8th August 2017

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https://www.nature.com/articles/s41598-017-10410-1
Original languageEnglish
Pages (from-to)10633
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - 6 Sep 2017

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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