11{beta}-Hydroxysteroid dehydrogenases control access of 7{beta},27-dihydroxycholesterol to retinoid-related orphan receptor {gamma} [Research Articles]

We examined the role of 11β-HSDs in the enzymatic control of the intracellular availability of 7β,27-dihydroxycholesterol (7β27OHC), a retinoid-related orphan receptor (ROR) ligand. We used microsomal preparations of cells expressing recombinant 11β-HSD1 and 11β-HSD2 to assess whether 7β27OHC and 7-keto,27-hydroxycholesterol (7k27OHC) are substrates of these enzymes. Binding of 7β27OHC and 7k27OHC to 11β-HSDs was studied by molecular modeling. To our knowledge, the stereospecific oxoreduction of 7k27OHC to 7β27OHC by human 11β-HSD1 and the reverse oxidation reaction of 7β27OHC to 7k27OHC by human 11β-HSD2 were demonstrated for the first time. Apparent enzyme affinities of 11β-HSDs for these novel substrates were equal to or higher than those of the glucocorticoids. This is supported by the fact that 7k27OHC and 7β27OHC are potent inhibitors of the 11β-HSD1-dependent oxoreduction of cortisone and the 11β-HSD2-dependent oxidation of cortisol, respectively. Furthermore, molecular docking calculations explained stereospecific enzyme activities. Finally, using an inducible ROR reporter system, we showed that 11β-HSD1 and 11β-HSD2 controlled ROR activity. These findings revealed a novel glucocorticoid-independent prereceptor regulation mechanism by 11β-HSDs that warrants further investigation.

Source: The Journal of Lipid Research - August 31, 2019 Category: Lipidology Authors: Beck, K. R., Inderbinen, S. G., Kanagaratnam, S., Kratschmar, D. V., Jetten, A. M., Yamaguchi, H., Odermatt, A. Tags: Research Articles Source Type: research