11β-Hydroxysteroid Dehydrogenase Type 1: A Potential Therapeutic Target for the Control of Local Glucocorticoid Concentrations

Alex      Odermatt

doi:10.2174/1573408054022252

Abstract

Chronically elevated glucocorticoid concentrations, either systemically or locally, are associated with adverse metabolic effects, including osteoporosis, Cushings syndrome, obesity, dyslipidemia, type 2 diabetes, and cardiovascular disease. Elevated glucocorticoid levels impair insulin and leptin sensitivity, ultimately resulting in the development of the metabolic syndrome. β-hydroxysteroid dehydrogenase type 1 (β-HSD1) catalyzes the oxoreduction of inactive 11-ketoglucocorticoids (cortisone in humans, 11- dehydrocorticosterone in rodents) to active β-hydroxyglucocorticoids (cortisol in humans, corticosterone in rodents) and regulates the local activation of glucocorticoid receptors (GR). Studies in transgenic mice demonstrated a causal role of β-HSD1 for the development of the metabolic syndrome. In humans, β-HSD1 expression and visceral obesity positively correlate, making this enzyme a promising target for therapeutic interventions. Administration of a selective synthetic non-steroidal β-HSD1 inhibitor lowered circulating glucose and increased insulin sensitivity in hyperglycemic mouse models. Moreover, agonists of PPARg and LXRα, used in diabetes treatment, decrease β-HSD1 expression, suggesting that some of the beneficial metabolic effects of these anti-diabetic drugs may be due to reduced local GR activation. In addition to its role in the activation of glucocorticoids, β-HSD1 catalyzes the detoxification of reactive carbonyl-compounds, including the major dietary oxysterol 7-ketocholesterol, the potent tobacco carcinogen nicotine-derived nitrosamine ketone (NNK) and the anti-cancer drug oracin. To achieve efficient and safe therapeutic treatment further studies have to address the structure-function relationship of β-HSD1 and the pathophysiological relevance of this enzyme in detoxification processes. Appropriate dosing and tissue-specific delivery or activity of highly selective β-HSD1 inhibitors may be required for successful clinical applications.

Keywords: βeta-hydroxysteroid dehydrogenase, glucocorticoid, cortisol, obesity, metabolic syndrome