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

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5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. / Nasiri, Maryam; Nikolaou, Nikolaos; Parajes Castro, Silvia; Krone, Nils P; Valsamakis, George; Mastorakos, George; Hughes, Beverly; Taylor, Angela; Bujalska, Iwona J; Gathercole, Laura L; Tomlinson, Jeremy W.

In: Endocrinology, Vol. 156, No. 8, 14.05.2015, p. 2863-71.

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@article{3d321cbebfd04db88130064a43ed2531,
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.",
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",
author = "Maryam Nasiri and Nikolaos Nikolaou and {Parajes Castro}, Silvia and Krone, {Nils P} and George Valsamakis and George Mastorakos and Beverly Hughes and Angela Taylor and Bujalska, {Iwona J} and Gathercole, {Laura L} and Tomlinson, {Jeremy W}",
year = "2015",
month = may,
day = "14",
doi = "10.1210/en.2015-1149",
language = "English",
volume = "156",
pages = "2863--71",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "Endocrine Society",
number = "8",

}

RIS

TY - JOUR

T1 - 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes

AU - Nasiri, Maryam

AU - Nikolaou, Nikolaos

AU - Parajes Castro, Silvia

AU - Krone, Nils P

AU - Valsamakis, George

AU - Mastorakos, George

AU - Hughes, Beverly

AU - Taylor, Angela

AU - Bujalska, Iwona J

AU - Gathercole, Laura L

AU - Tomlinson, Jeremy W

PY - 2015/5/14

Y1 - 2015/5/14

N2 - 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.

AB - 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.

KW - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase

KW - 5-alpha Reductase Inhibitors

KW - Adult

KW - Aged

KW - Androgens

KW - Biological Transport

KW - Cells, Cultured

KW - Female

KW - Finasteride

KW - Glucocorticoids

KW - Hepatocytes

KW - Humans

KW - Insulin

KW - Lipogenesis

KW - Male

KW - Membrane Proteins

KW - Middle Aged

KW - Phenotype

U2 - 10.1210/en.2015-1149

DO - 10.1210/en.2015-1149

M3 - Article

C2 - 25974403

VL - 156

SP - 2863

EP - 2871

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 8

ER -