5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes

Research output: Contribution to journalArticle

Authors

  • Maryam Nasiri
  • Nikolaos Nikolaou
  • George Valsamakis
  • George Mastorakos
  • Beverly Hughes
  • Jeremy Tomlinson

External organisations

  • Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department, Aretaieion University Hospital, Athens Medical School, Athens

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.

Details

Original languageEnglish
Pages (from-to)2863-71
Number of pages9
JournalEndocrinology
Volume156
Issue number8
Early online date14 May 2015
Publication statusE-pub ahead of print - 14 May 2015

Keywords

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Adult, Aged, Androgens, Biological Transport, Cells, Cultured, Female, Finasteride, Glucocorticoids, Hepatocytes, Humans, Insulin, Lipogenesis, Male, Membrane Proteins, Middle Aged, Phenotype