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DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins
Zoltan Balazs1, Roberto A S Schweizer, Felix J Frey
1Institute of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Journal of the American Society of Nephrology : JASN
|November 23, 2007
Summary
Dehydroepiandrosterone (DHEA) enhances 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity, shifting glucocorticoid conversion towards inactivation. This study reveals a mechanism for DHEA's antiglucocorticoid effects.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2 interconvert active and inactive glucocorticoids.
- Dysregulation of 11beta-HSD enzymes is linked to obesity, diabetes, hypertension, and cardiovascular disease.
- Dehydroepiandrosterone (DHEA) exhibits antiglucocorticoid effects, but the mechanism remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying DHEA's antiglucocorticoid effects.
- To investigate the impact of DHEA on 11beta-HSD type 1 and type 2 expression and activity.
- To identify key regulatory pathways involved in DHEA-mediated modulation of glucocorticoid metabolism.
Main Methods:
- Cell culture experiments using a rat cortical collecting duct cell line.
- In vivo studies involving C57BL/6J mice and Sprague-Dawley rats.
- Analysis of mRNA and protein expression, enzyme activity assays, and Western blotting.
Main Results:
- DHEA treatment significantly increased 11beta-HSD2 mRNA expression and activity in vitro and in vivo.
- DHEA administration led to a trend of reduced urinary corticosterone to 11-dehydrocorticosterone ratios in rats.
- DHEA modulated 11beta-HSD2 transcription via a phosphatidylinositol-3 kinase/Akt-dependent pathway, increasing C/EBP-beta expression.
Conclusions:
- DHEA induces a shift in enzyme expression favoring 11beta-HSD2 over 11beta-HSD1.
- This shift enhances the conversion of active to inactive glucocorticoids, explaining DHEA's antiglucocorticoid properties.
- CCAAT/enhancer-binding protein-alpha and -beta are identified as key regulators of HSD11B2 transcription, differentially controlling 11beta-HSD1 and 11beta-HSD2 expression.
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