2. Academic Validation
  3. Characterization of 5α-reductase activity and isoenzymes in human abdominal adipose tissues

Characterization of 5α-reductase activity and isoenzymes in human abdominal adipose tissues

  • J Steroid Biochem Mol Biol. 2016 Jul;161:45-53. doi: 10.1016/j.jsbmb.2016.02.003.
Mohamed Fouad Mansour 1,  Mélissa Pelletier 2,  André Tchernof 3
Affiliations

Affiliations

  • 1 Endocrinology and Nephrology, CHU de Québec Medical Center, Québec, Canada; Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
  • 2 Endocrinology and Nephrology, CHU de Québec Medical Center, Québec, Canada; Québec Heart and Lung Institute Research Center, Laval University, Québec, Canada.
  • 3 Endocrinology and Nephrology, CHU de Québec Medical Center, Québec, Canada; Québec Heart and Lung Institute Research Center, Laval University, Québec, Canada; School of Nutrition, Laval University, Québec, Canada. Electronic address: andre.tchernof@crchudequebec.ulaval.ca.
PMID: 26855069 DOI: 10.1016/j.jsbmb.2016.02.003
Abstract

Introduction: The substrate for the generation of 5α-dihydrotestosterone (DHT) is either androstenedione (4-dione) which is first converted to androstanedione and then to DHT through 17-oxoreductase activity, or testosterone, which is directly converted to DHT. Three 5α-reductase isoenzymes have been characterized and designated as types 1, 2 and 3 (SRD5A1, 2 and 3).

Objective: To define the predominant source of local DHT production in human adipose tissues, identify 5α-reductase isoenzymes and test their impact on preadipocyte differentiation.

Methods: Cultures of omental (OM) and subcutaneous (SC) preadipocytes were treated for 0, 6 or 24h with 30nM (14)C-4-dione or (14)C-testosterone, with and without 500nM 5α-reductase inhibitors 17-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androstan-3-one (4-MA) or finasteride. Protein level and mRNA abundance of 5α-reductase isoenzymes/transcripts were examined in whole SC and OM adipose tissue. HEK-293 cells stably transfected with 5α-reductase type 1, 2 or 3 were used to test 5α-reductase inhibitors. We also assessed the impact of 5α-reductase inhibitors on preadipocyte differentiation.

Results: Over 24h, DHT formation from 4-dione increased gradually (p<0.05) and was significantly higher compared to that generated from testosterone (p<0.001). DHT formation from both 4-dione and testosterone was blocked by both 5α-reductase inhibitors. In whole adipose tissue from both fat compartments, SRD5A3 was the most highly expressed isoenzyme followed by SRD5A1 (p<0.001). SRD5A2 was not expressed. In HEK-293 cells, 4-MA and finasteride inhibited activity of 5α-reductases types 2 and 3 but not type 1. In preadipocyte cultures where differentiation was inhibited by 4-dione (p<0.05, n=7) or testosterone (p<0.05, n=5), the inhibitors 4-MA and finasteride abolished these effects.

Conclusion: Although 4-dione is the main source of DHT in human preadipocytes, production of this steroid by 5α-reductase isoenzymes mediates the inhibitory effect of both 4-dione and testosterone on preadipocyte differentiation.

Keywords

5α-reductase; Adipose tissue; Androstenedione; Dihydrotestosterone; Testosterone.

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