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Nathan Appanna Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK

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Hylton Gibson Department of Biochemistry, Stellenbosch University, Stellenbosch, Western Cape, South Africa

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Elena Gangitano Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK
Department of Experimental Medicine, Sapienza University of Rome, Rome, Lazio, Italy

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Niall J Dempster Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK

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Karen Morris Biochemistry Department, Manchester University NHS Trust, Manchester Academic Health Science Centre, Manchester, Greater Manchester, UK

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Sherly George Biochemistry Department, Manchester University NHS Trust, Manchester Academic Health Science Centre, Manchester, Greater Manchester, UK

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Anastasia Arvaniti Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, Oxfordshire, UK

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Laura L Gathercole Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, Oxfordshire, UK

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Brian Keevil Biochemistry Department, Manchester University NHS Trust, Manchester Academic Health Science Centre, Manchester, Greater Manchester, UK

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Trevor M Penning Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

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Karl-Heinz Storbeck Department of Biochemistry, Stellenbosch University, Stellenbosch, Western Cape, South Africa

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Jeremy W Tomlinson Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK

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Nikolaos Nikolaou Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, Oxfordshire, UK

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Steroid hormones, including glucocorticoids and androgens, exert a wide variety of effects in the body across almost all tissues. The steroid A-ring 5β-reductase (AKR1D1) is expressed in human liver and testes, and three splice variants have been identified (AKR1D1-001, AKR1D1-002, AKR1D1-006). Amongst these, AKR1D1-002 is the best described; it modulates steroid hormone availability and catalyses an important step in bile acid biosynthesis. However, specific activity and expression of AKR1D1-001 and AKR1D1-006 are unknown. Expression of AKR1D1 variants were measured in human liver biopsies and hepatoma cell lines by qPCR. Their three-dimensional (3D) structures were predicted using in silico approaches. AKR1D1 variants were overexpressed in HEK293 cells, and successful overexpression confirmed by qPCR and Western blotting. Cells were treated with either cortisol, dexamethasone, prednisolone, testosterone or androstenedione, and steroid hormone clearance was measured by mass spectrometry. Glucocorticoid and androgen receptor activation were determined by luciferase reporter assays. AKR1D1-002 and AKR1D1-001 are expressed in human liver, and only AKR1D1-006 is expressed in human testes. Following overexpression, AKR1D1-001 and AKR1D1-006 protein levels were lower than AKR1D1-002, but significantly increased following treatment with the proteasomal inhibitor, MG-132. AKR1D1-002 efficiently metabolised glucocorticoids and androgens and decreased receptor activation. AKR1D1-001 and AKR1D1-006 poorly metabolised dexamethasone, but neither protein metabolised cortisol, prednisolone, testosterone or androstenedione. We have demonstrated the differential expression and role of AKR1D1 variants in steroid hormone clearance and receptor activation in vitro. AKR1D1-002 is the predominant functional protein in steroidogenic and metabolic tissues. In addition, AKR1D1-001 and AKR1D1-006 may have a limited, steroid-specific role in the regulation of dexamethasone action.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/JME-20-0160
Volume/Issue:
Volume 66: Issue 3
Open access