11 beta-HYDROXYSTEROID DEHYDROGENASES: INTRACELLULAR GATE-KEEPERS OF TISSUE GLUCOCORTICOID ACTION

Abstract

Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11 beta-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11 beta-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11 beta-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11 beta-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11 beta-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. 11 beta-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11 beta-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11 beta-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 11 beta-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11 beta-HSD2 as a marker of programming is being explored. The 11 beta-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.