Cargando…

Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man

CONTEXT: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have...

Descripción completa

Detalles Bibliográficos
Autores principales: Hazlehurst, Jonathan M., Oprescu, Andrei I., Nikolaou, Nikolaos, Di Guida, Riccardo, Grinbergs, Annabel E. K., Davies, Nigel P., Flintham, Robert B., Armstrong, Matthew J., Taylor, Angela E., Hughes, Beverly A., Yu, Jinglei, Hodson, Leanne, Dunn, Warwick B., Tomlinson, Jeremy W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701851/
https://www.ncbi.nlm.nih.gov/pubmed/26574953
http://dx.doi.org/10.1210/jc.2015-2928
_version_ 1782408544400703488
author Hazlehurst, Jonathan M.
Oprescu, Andrei I.
Nikolaou, Nikolaos
Di Guida, Riccardo
Grinbergs, Annabel E. K.
Davies, Nigel P.
Flintham, Robert B.
Armstrong, Matthew J.
Taylor, Angela E.
Hughes, Beverly A.
Yu, Jinglei
Hodson, Leanne
Dunn, Warwick B.
Tomlinson, Jeremy W.
author_facet Hazlehurst, Jonathan M.
Oprescu, Andrei I.
Nikolaou, Nikolaos
Di Guida, Riccardo
Grinbergs, Annabel E. K.
Davies, Nigel P.
Flintham, Robert B.
Armstrong, Matthew J.
Taylor, Angela E.
Hughes, Beverly A.
Yu, Jinglei
Hodson, Leanne
Dunn, Warwick B.
Tomlinson, Jeremy W.
author_sort Hazlehurst, Jonathan M.
collection PubMed
description CONTEXT: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified. OBJECTIVE: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism. DESIGN: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry. SETTING: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. MAIN OUTCOME MEASURE: Incorporation of hepatic lipid was measured with MRS. RESULTS: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism. CONCLUSIONS: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.
format Online
Article
Text
id pubmed-4701851
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Endocrine Society
record_format MEDLINE/PubMed
spelling pubmed-47018512016-02-08 Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man Hazlehurst, Jonathan M. Oprescu, Andrei I. Nikolaou, Nikolaos Di Guida, Riccardo Grinbergs, Annabel E. K. Davies, Nigel P. Flintham, Robert B. Armstrong, Matthew J. Taylor, Angela E. Hughes, Beverly A. Yu, Jinglei Hodson, Leanne Dunn, Warwick B. Tomlinson, Jeremy W. J Clin Endocrinol Metab Original Articles CONTEXT: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified. OBJECTIVE: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism. DESIGN: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry. SETTING: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. MAIN OUTCOME MEASURE: Incorporation of hepatic lipid was measured with MRS. RESULTS: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism. CONCLUSIONS: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation. Endocrine Society 2016-01 2015-11-17 /pmc/articles/PMC4701851/ /pubmed/26574953 http://dx.doi.org/10.1210/jc.2015-2928 Text en https://creativecommons.org/licenses/by/4.0/ This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s)
spellingShingle Original Articles
Hazlehurst, Jonathan M.
Oprescu, Andrei I.
Nikolaou, Nikolaos
Di Guida, Riccardo
Grinbergs, Annabel E. K.
Davies, Nigel P.
Flintham, Robert B.
Armstrong, Matthew J.
Taylor, Angela E.
Hughes, Beverly A.
Yu, Jinglei
Hodson, Leanne
Dunn, Warwick B.
Tomlinson, Jeremy W.
Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title_full Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title_fullStr Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title_full_unstemmed Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title_short Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man
title_sort dual-5α-reductase inhibition promotes hepatic lipid accumulation in man
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701851/
https://www.ncbi.nlm.nih.gov/pubmed/26574953
http://dx.doi.org/10.1210/jc.2015-2928
work_keys_str_mv AT hazlehurstjonathanm dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT oprescuandreii dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT nikolaounikolaos dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT diguidariccardo dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT grinbergsannabelek dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT daviesnigelp dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT flinthamrobertb dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT armstrongmatthewj dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT taylorangelae dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT hughesbeverlya dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT yujinglei dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT hodsonleanne dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT dunnwarwickb dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman
AT tomlinsonjeremyw dual5areductaseinhibitionpromoteshepaticlipidaccumulationinman