ECE2015 Symposia Glucocorticoid action in health and disease (3 abstracts)
University of Basel, Basel, Switzerland.
11β-hydoxysteroid dehydrogenase type 1 (11β-HSD1) essentially catalyzes the conversion of the inactive endogenous glucocorticoid cortisone (11-dehydrocorticosterone in rodents) and the synthetic prednisone into the active cortisol (corticosterone in rodents) and prednisolone. The association of an elevated expression of 11β-HSD1 with metabolic disease has been extensively studied in humans and in rodent models. It is generally assumed that the effects that are observed upon modulating 11β-HSD1 function by pharmacological inhibition or genetic manipulation in transgene mouse models are glucocorticoid-dependent. However, 11β-HSD1 is a multi-functional carbonyl reductase involved in the hepatic metabolism of various non-steroidal xenobiotics. Besides, it has a role in the metabolism of neurosteroids, oxidized cholesterol and bile acids. In as much these alternative substrates might affect 11β-HSD1-dependent glucocorticoid activation can, so far, only be estimated from in vitro studies, and further investigations in vivo are needed.
A recent study in 11β-HSD1 deficient mice revealed elevated concentrations of circulating free bile acids, an effect that was more pronounced in global than liver-specific knockout mice. A reduced expression of the bile acid coenzyme A ligase Fatp5 suggested an impaired bile acid amidation and subsequently decreased conjugation. These effects of the lack of 11β-HSD1 activity seem to be glucocorticoid-independent because intra-hepatic corticosterone levels and glucocorticoid receptor target gene expression were not decreased in livers from liver-specific knockout mice. Furthermore, Fatp5 expression was not altered in mice deficient in hepatic glucocorticoid receptors.
Thus, the elucidation of glucocorticoid-independent functions of 11β-HSD1, such as its role in oxysterol and bile acid homeostasis, and the relevance for metabolic and immune disorders warrants further investigations.