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Abstract
Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.
Original language | English |
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Pages (from-to) | 1139-1206 |
Number of pages | 68 |
Journal | Physiological reviews |
Volume | 93 |
Issue number | 3 |
DOIs | |
Publication status | Published - Jul 2013 |
Keywords / Materials (for Non-textual outputs)
- 11-beta-Hydroxysteroid Dehydrogenases
- Animals
- Gene Expression Regulation, Enzymologic
- Glucocorticoids
- Humans
- Receptors, Glucocorticoid
- Receptors, Mineralocorticoid
- Tissue Distribution
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- 1 Finished
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How does 11B-hydroxysteriod dehydrogenase type 1 limit inflammation.
Chapman, K., Gray, M., Savill, J. & Seckl, J.
1/10/08 → 30/04/12
Project: Research