Readjusting the Glucocorticoid Balance: An Opportunity for Modulators of 11β -Hydroxysteroid Dehydrogenase Type 1 Activity?

Atanas   G.   Atanasov; Alex      Odermatt

Abstract

Glucocorticoids play a pivotal role in the regulation of most essential physiological processes, including energy metabolism, maintenance of electrolyte balance and blood pressure, immune-modulation and stress responses, cell proliferation and differentiation, as well as regulation of memory and cognitive functions. There are several levels at which glucocorticoid action can be modulated. On a tissue-specific level, glucocorticoid action is tightly controlled by 11β- hydroxysteroid dehydrogenase (11β-HSD) enzymes. The conversion of inactive 11-ketoglucocorticoids (cortisone and 11- dehydrocorticosterone) into active 11β-hydroxyglucocorticoids (cortisol and corticosterone) is catalyzed by 11β-HSD1, which is expressed in many tissues and plays an important role in metabolically relevant tissues such as the liver, adipose tissue and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11β-HSD1 activity rather than elevated systemic glucocorticoid levels has been associated with metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that compounds inhibiting 11β-HSD1 activity ameliorate the adverse effects of excessive glucocorticoid concentrations on metabolic processes, providing promising opportunities for the development of therapeutic interventions. This review addresses recent findings relevant for the development and application of therapeutically useful compounds that modulate 11β-HSD1 function.

Keywords: 11β-hydroxysteroid dehydrogenase, glucocorticoid, cortisol, obesity, metabolic syndrome, drug development, inhibitor

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