Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2003) 5 P236

BES2003 Poster Presentations Steroids (39 abstracts)

Regulation of the human 11beta-hydroxysteroid dehydrogenase gene by glucocorticoids

O Bedendo 2 , IJ Bujalska 1 , N Draper 1 , EA Walker 1 , M Hewison 1 , F Mantero 2 & PM Stewart 1

1Division of Medical Sciences, University of Birmingham, Birmingham, UK; 2Division of Endocrinology, Dept of Medical and Surgical Sciences, University of Padua, Padua, Italy.

Glucocorticoids regulate transcription of many genes through the binding to the glucocorticoid receptor (GR) however, their intracellular levels are tightly regulated by the microsomal enzyme 11beta-hydroxysteroid dehydrogenase. Two isozymes of this enzyme have been cloned and characterised; 11beta- hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which is mainly expressed in the liver and adipose tissue and 11beta-HSD type 2 expressed in the kidney and placenta. Within 2.5kb of human 11beta-HSD1 promoter region there are five putative glucocorticoid responsive elements potentially involved in glucocorticoid gene regulation. To decipher the mechanisms that regulate 11beta-HSD1 gene induction at the transcriptional level, we carried out transfection studies using four fragments encoding -2506 to +83 (2506pr), -1382 to +83 (1382pr), -804 to +83 (804pr) and -301 to +83 (301pr) of human 11beta-HSD type 1 promoter (11beta-HSD1pr), cloned into the pGL3-enhancer vector. Luciferase activities were measured following transient transfection of the human embryonic liver cell line, WRL68. Basal luciferase activities (fold-increase above control levels, n=3) were significantly higher for the 301pr (1.89±0.30), 804pr (1.79±0.15) and 1382pr (2.33±0.12; mean±se, p<0.05) promoter constructs. Luciferase activity reverted to control levels (0.71±0.13) for 2506pr, suggesting that potent suppressor elements may exist in the 5' promoter region between -1382 and -2506bp. Since our previous studies showed up-regulation of 11beta-HSD1 expression in human preadipocytes by cortisol, the effect of glucocorticoids on our human 11beta-HSD1pr constructs was investigated. We observed an induction of luciferase activity, above control levels, of 2.57±0.18-fold for 301pr, 2.25±0.18-fold for 802pr and 2.09±0.03-fold (mean±se, p<0.05) for 1382pr by 100nM cortisol. This effect of cortisol was diminished when cells were transfected with the 2506pr construct (1.22±0.03). These data demonstrate the glucocorticoid induction of human 11beta-HSD1 gene expression. 11beta-HSD1 has emerged as a novel therapeutic target to improve insulin sensitivity and obesity by inhibiting cortisol generation locally within liver and adipose tissue.

Volume 5

22nd Joint Meeting of the British Endocrine Societies

British Endocrine Societies 

Browse other volumes

Article tools

My recent searches

No recent searches.