Enzymatic interconversion of the oxysterols 7β, 25-dihydroxycholesterol and 7-keto, 25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2. Issue 190 (June 2019)

• Record Type: Journal Article
• Authors: Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 190(2019)
• Page Start: 19
• Page End: 28
• Publication Date: 2019-06
• Subjects: 7α25OHC 7α, 25-dihydroxycholesterol -- 7β25OHC 7β, 25-dihydroxycholesterol -- 7k25OHC 7-keto, 25-hydroxycholesterol -- 7βOHC 7β-hydroxycholesterol -- 7kC 7-ketocholesterol -- 7oxoLCA 7-oxolithocholic acid -- 11β-HSD1 11β-hydroxysteroid dehydrogenase type 1 -- 11β-HSD2 11β-hydroxysteroid dehydrogenase type 2 -- 25OHC 25-hydroxycholesterol -- CDCA chenodeoxycholic acid -- CH25H cholesterol 25-hydroxylase -- CT cholestane-3β, 5α, 6β-triol -- CYP7B1 cytochrome P450 7B1 -- EBI2 Epstein-Barr virus-induced gene 2 -- GA glycyrrhetinic acid -- GPCR G-protein-coupled receptor -- GR glucocorticoid receptor -- H6PD hexose-6-phosphate dehydrogenase -- IBD inflammatory bowel disease -- OCDO 6-oxo-cholestane-3β, 5α-diol -- Smo Smoothened; Oxysterol -- 11beta-hydroxysteroid dehydrogenase -- Metabolism -- Epstein-Barr virus-induced gene 2 -- 7-ketocholesterol -- Cholesterol 25-hydroxylase; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.03.011
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: hydroxylation of 7-ketocholesterol to 7-keto, 25-hydroxycholesterol (7k25OHC) by CH25H. stereospecific reduction of 7k25OHC to 7β, 25-dihydroxycholesterol (7β25OHC) by 11β-HSD1. oxidation of 7β25OHC to 7k25OHC catalyzed by 11β-HSD2. 7k25OHC may not be a physiological relevant ligand for EBI2. novel glucocorticoid-independent pre-receptor regulation mediated by 11β-HSDs. 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.