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Pr. Alex ODERMATT / Role of 11β-hydroxysteroid dehydrogenase enzymes in oxysterol and bile acid metabolism
15 février 2019 @ 11:00 - 13:30
Pr. Alex ODERMATT, University of Basel, Switzerland
11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2 are well known to control the cell- and tissue-specific interconversion of inactive and active glucocorticoids. Besides, these enzymes represent a link between glucocorticoid and oxysterol and bile acid homeostasis. Several bile acids inhibit 11β-HSDs and we recently demonstrated that 11β-HSD1 catalyzes the conversion of 7-oxolithocholic acid to chenodeoxycholic acid. Furthermore, a role for 11β-HSD1 in the metabolism of 7-oxocholesterol (7kC) could be demonstrated. However, no endogenous receptor has been identified so far for 7kC or its metabolite 7β-hydroxycholesterol, in contrast to the known receptors for 7α,25-dihydroxycholesterol (7α25OHC), i.e. Epstein-Barr virus-induced gene 2 (EBI2), or 7β,27-dihydroxycholesterol (7β27OHC), i.e. retinoic acid related orphan receptor (ROR)γ. In order to unravel the underlying enzymatic control of the formation of such dihydroxylated oxysterols, we studied the role of 11β-HSD1 and 11β-HSD2 in their metabolism. We found a stereospecific and seemingly irreversible oxoreduction of 7-keto,25-hydroxycholesterol (7k25OHC) and 7-keto,27-hydroxycholesterol (7k27OHC) to their corresponding 7β-hydroxylated metabolites 7β25OHC and 7β25OHC by human 11β-HSD1 in vitro. Additionally, we found that 11β-HSD2 catalyzes the reverse reaction. Both 11β-HSD1- and 11β-HSD2-dependent glucocorticoid metabolism was inhibited by the respective oxysterol. Future research should address the physiological relevance such as a contribution of these oxysterols to the pathogenesis of hepatic steatosis by regulation of RORγ or to the migration of immune cells by EBI2 activation.