Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Abstract

Oxysterols are cholesterol metabolites derived through either autoxidation or enzymatic processes. They consist of a large family of bioactive lipids that have been associated with the progression of multiple pathologies. In order to unravel (patho-)physiological mechanisms involving oxysterols, it is crucial to elucidate the underlying formation and degradation of oxysterols. A role of 11β-hydroxysteroid dehydrogenases (11β-HSDs) in oxysterol metabolism by catalyzing the interconversion of 7-ketocholesterol (7kC) and 7β-hydroxycholesterol (7βOHC) has already been reported. The present study addresses a function of 11β-HSD1 in the enzymatic generation of 7β,25-dihydroxycholesterol (7β25OHC) from 7-keto,25-hydroxycholesterol (7k25OHC) and tested whether 11β-HSD2 is able to catalyze the reverse reaction. For the first time, using recombinant enzymes, the formation of 7k25OHC from 7kC by cholesterol 25-hydroxylase (CH25H) and further stereospecific oxoreduction to 7β25OHC by human and mouse 11β-HSD1 could be demonstrated. Additionally, experiments using human 11β-HSD2 showed the oxidation of 7β25OHC to 7k25OHC. Molecular modeling provided an explanation for the stereospecific interconversion of 7β25OHC and 7k25OHC. Production of the Epstein-Barr virus-induced gene 2 (EBI2) ligand 7β25OHC from 7k25OHC in challenged tissue by 11β-HSD1 may be important in inflammation. In conclusion, these results demonstrate a novel glucocorticoid-independent pre-receptor regulation mediated by 11β-HSDs.