Chenodeoxycholic acid and deoxycholic acid inhibit 11β-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor

Inappropriate activation of the mineralocorticoid receptor (MR) results in renal sodium retention and potassium loss in patients with liver cirrhosis. Recent evidence suggested that this MR activation is, at least in part, a result of bile acid-dependent reduction in 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) activity, an enzyme preventing cortisol-dependent activation of MR by converting cortisol to cortisone. Here, we investigated the molecular mechanisms underlying bile acid-mediated MR activation. Analysis of urinary bile acids from 12 patients with biliary obstruction revealed highly elevated concentrations of chenodeoxycholic acid (CDCA), cholic acid (CA), and deoxycholic acid (DCA), with average concentrations of 50-80 muM. Although CDCA and DCA both mediated nuclear translocation of MR in the absence of 11betaHSD2 and steroids in transiently expressing HEK-293 cells, the transcriptional activity of MR was not stimulated. In contrast, CDCA and DCA both inhibited 11betaHSD2 with IC50 values of 22 and 38 muM, respectively and caused cortisol-dependent nuclear translocation and increased transcriptional activity of MR. LCA, the bile acid that most efficiently inhibited 11betaHSD2, was present at very low concentrations in cholestatic patients, whereas the weak inhibitor CA did not cause MR activation. In conclusion, these findings indicate that CDCA, and to a lesser extent DCA, by inhibiting 11betaHSD2, mediate cortisol-dependent nuclear translocation and transcriptional activation of MR and are responsible at least for a part of the sodium retention and potassium excretion observed in patients with biliary obstruction.