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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