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Carbonyl reductase 1 catalyzes 20 beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
- Morgan, Ruth A. (author)
- Beck, Katharina R. (author)
- Nixon, Mark (author)
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- Homer, Natalie Z. M. (author)
- Crawford, Andrew A. (author)
- Melchers, Diana (author)
- Houtman, René (author)
- Meijer, Onno C. (author)
- Anderson, Anna J. (author)
- Upreti, Rita (author)
- Stimson, Roland H. (author)
- Michoel, Tom (author)
- Cohain, Ariella (author)
- Ruusalepp, Arno (author)
- Schadt, Eric E. (author)
- Andrew, Ruth (author)
- Kenyon, Christopher J. (author)
- Hadoke, Patrick W. F. (author)
- Odermatt, Alex (author)
- Keen, John A. (author)
- Walker, Brian R. (author)
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- (creator_code:org_t)
- 2017-09-06
- 2017
- English.
- In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
- Journal article (peer-reviewed)
Abstract
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- 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 20 beta-dihydrocortisol (20 beta-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 20 beta-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 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
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- Morgan, Ruth A.
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- Nixon, Mark
- Homer, Natalie Z ...
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- Melchers, Diana
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- Houtman, René
- Meijer, Onno C.
- Stomby, Andreas
- Anderson, Anna J ...
- Upreti, Rita
- Stimson, Roland ...
- Olsson, Tommy
- Michoel, Tom
- Cohain, Ariella
- Ruusalepp, Arno
- Schadt, Eric E.
- Björkegren, Joha ...
- Andrew, Ruth
- Kenyon, Christop ...
- Hadoke, Patrick ...
- Odermatt, Alex
- Keen, John A.
- Walker, Brian R.
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- MEDICAL AND HEALTH SCIENCES
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- Umeå University
- Karolinska Institutet
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