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

Sci Rep. 2017 Sep 6;7(1):10633. doi: 10.1038/s41598-017-10410-1.

Ruth A Morgan ¹ ², Katharina R Beck ³, Mark Nixon ⁴, Natalie Z M Homer ⁵, Andrew A Crawford ⁴ ⁶, Diana Melchers ⁷, René Houtman ⁷, Onno C Meijer ⁸, Andreas Stomby ⁹, Anna J Anderson ⁴, Rita Upreti ⁴, Roland H Stimson ⁴, Tommy Olsson ⁹, Tom Michoel ¹⁰, Ariella Cohain ¹¹, Arno Ruusalepp ¹² ¹³ ¹⁴, Eric E Schadt ¹¹, Johan L M Björkegren ¹¹ ¹² ¹³ ¹⁴ ¹⁵, Ruth Andrew ⁴ ⁵, Christopher J Kenyon ⁴, Patrick W F Hadoke ⁴, Alex Odermatt ³, John A Keen ¹⁶, Brian R Walker ⁴ ⁵

Affiliations

1 University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. [email protected].
2 Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK. [email protected].
3 Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
4 University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
5 Mass Spectrometry Core Laboratory, Wellcome Trust Clinical Research Facility, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
6 School of Social and Community Medicine, University of Bristol, Bristol, UK.
7 PamGene International, Den Bosch, The Netherlands.
8 Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
9 Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden.
10 The Roslin Institute, University of Edinburgh, Easter Bush Campus, Edinburgh, UK.
11 Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
12 Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia.
13 Clinical Gene Networks AB, Stockholm, Sweden.
14 Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
15 Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
16 Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.

PMID: 28878267 DOI: 10.1038/s41598-017-10410-1

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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