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<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>AKR1D1-001, AKR1D1-002, AKR1D1-006</jats:italic>). Amongst these, <jats:italic>AKR1D1-002</jats:italic> is the best described; it modulates steroid hormone availability and catalyses an important step in bile acid synthesis. However, specific activity and expression of <jats:italic>AKR1D1-001</jats:italic> and <jats:italic>AKR1D1-006</jats:italic> are unknown.</jats:p><jats:p><jats:italic>AKR1D1-002, AKR1D1-001</jats:italic> and <jats:italic>AKR1D1-006</jats:italic> were measured in human liver biopsies and human hepatoma cell lines by qPCR. Three-dimensional (3D) structures of <jats:italic>AKR1D1</jats:italic> variants were determined using <jats:italic>in silico</jats:italic> approaches. <jats:italic>AKR1D1</jats:italic> variants were over-expressed in HEK293 cells, and successful overexpression confirmed by qPCR and western blotting. Steroid hormone clearance was measured by mass spectrometry and ELISA, and steroid receptor activation determined by luciferase reporter assays.</jats:p><jats:p><jats:italic>AKR1D1-002</jats:italic> and <jats:italic>AKR1D1-001</jats:italic> are expressed in human liver, and only <jats:italic>AKR1D1-006</jats:italic> is expressed in human testes. Following over-expression in HEK293 cells, 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 or testosterone.</jats:p><jats:p>We have demonstrated the differential expression and role of <jats:italic>AKR1D1</jats:italic> splice variants to regulate steroid hormone clearance and receptor activation. AKR1D1-002 is the predominant functional protein in steroidogenic and metabolic tissues. In addition, AKR1D1-001 and AKR1D1-006 may have a limited role in the regulation of synthetic glucocorticoid action.</jats:p>

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Journal article


Cold Spring Harbor Laboratory

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