SFEBES2014 Oral Communications Steroids (6 abstracts)
Lack of 11β-hydroxysteroid dehydrogenase type 1 ameliorates the adverse features of Cushing's syndrome
Stuart Morgan 1 , Emma McCabe 1 , Laura Gathercole 1 , Zaki Hassan-Smith 1 , Dean Larner 1 , Iwona Bujalska 1 , Paul Stewart 1,2 , Jeremy Tominson 1 & Gareth Lavery 1
1University of Birmingham, Birmingham, UK; 2University of Leeds, Leeds, UK.
Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have a significant adverse effect profile, leading to a Cushingoid phenotype. In the present study, we test the hypothesis that reactivation of glucocorticoids, in peripheral tissues by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), is a major determinant of exogenous Cushing’s syndrome.
WT, global 11β-HSD1 knockout (GKO), liver-specific 11β-HSD1 knockout (LKO) and fat-specific 11β-HSD1 knockout (FKO) mice were treated with corticosterone (100 μg/ml) or vehicle via drinking water for 5 weeks.
Corticosterone treated WT and global GKO mice had grossly elevated serum corticosterone levels. However, GKO mice were protected from Cushingoid features, as indicated by reversal of glucose intolerance, hyperinsulinaemia, systolic hypertension, increased adiposity, myoatrophy and dermal atrophy. Corticosterone increased expression of the lipolytic enzymes: hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in adipose tissue of WT mice, paralleled by increased serum free fatty acids (FFAs) and hepatic steatosis, whilst GKO mice were completely protected from the hepatic manifestations of corticosterone treatment. Similarly, in corticosterone-treated FKO mice, reversal of increased ATGL and HSL in adipose tissue, increased serum FFAs and hepatic steatosis was demonstrated, but no protection from the impact of corticosterone was observed in LKO mice.
These data demonstrate that glucocorticoids, reactivated by 11β-HSD1 in peripheral tissues, are a major determinant of Cushingoid features in corticosteroid treated mice. Furthermore, local glucocorticoid regeneration in adipose tissue, and not liver, is central in driving the hepatic manifestations of glucocorticoid excess. 11β-HSD1 is an exciting therapeutic target for patients with Cushing’s syndrome.
Volume 34
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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