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

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