title: 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes.
abstract: Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Maryam
authors.initials: M
authors.lastname: Nasiri
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Nikolaou
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parajes
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Nils P
authors.initials: NP
authors.lastname: Krone
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Valsamakis
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Mastorakos
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Beverly
authors.initials: B
authors.lastname: Hughes
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Angela
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Iwona J
authors.initials: IJ
authors.lastname: Bujalska
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gathercole
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000502:physiology*; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000728:Androgens / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008875:Middle Aged; D010641:Phenotype
chemical_list: D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D005938:Glucocorticoids; D007328:Insulin; D008565:Membrane Proteins; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human