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Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 drives concurrent

Lina Schiffer1, Imken Oestlund2, Jacky L Snoep2,3

  • 1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 29, 2024
PubMed

Insights

11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) inhibits the production of the potent androgen 11-ketotestosterone (11KT) in adipose tissue. Inhibiting HSD11B1 increases 11KT levels, potentially offsetting therapeutic benefits in women.

Area of Science:

  • Endocrinology
  • Metabolic Research
  • Steroid Biochemistry

Background:

  • Aldo-keto reductase 1C3 (AKR1C3) activates androgens.
  • 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) inactivates 11-oxygenated androgens and activates glucocorticoids.
  • HSD11B1 and AKR1C3 are co-expressed in adipose tissue, suggesting potential counteracting roles.

Purpose of the Study:

  • To investigate the interaction between HSD11B1 and AKR1C3 in 11-oxygenated androgen biosynthesis.
  • To determine the effect of HSD11B1 inhibition on 11-ketotestosterone (11KT) production in human adipose tissue and systemically.
  • To assess the clinical implications of HSD11B1 inhibition in women, particularly concerning androgen metabolism.

Main Methods:

  • In vitro enzymatic assays and in silico modeling to study HSD11B1 and AKR1C3 interactions.
  • Ex vivo incubations of human female adipose tissue samples.
  • Clinical study involving type 2 diabetes patients receiving a selective HSD11B1 inhibitor (AZD4017).

Main Results:

  • HSD11B1 was shown to attenuate AKR1C3-mediated biosynthesis of 11KT.
  • Inhibition of HSD11B1 in human adipose tissue ex vivo led to increased 11KT biosynthesis.
  • Systemic 11KT concentrations increased 2-3 fold in individuals treated with an HSD11B1 inhibitor.

Conclusions:

  • HSD11B1 plays a protective role against excessive 11KT production in adipose tissue.
  • HSD11B1 inhibition increases peripheral 11KT generation, which may counteract therapeutic benefits of HSD11B1 inhibitors in women.
  • Increased 11KT due to HSD11B1 inhibition could offset positive effects of glucocorticoid modulation in women.
Keywords:
11‐ketotestosteroneadipose tissuealdo‐keto reductase 1C3 (AKR1C3)intracrinologymetabolic syndrome

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