Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-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 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) 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 microm. Although CDCA and DCA both mediated nuclear translocation of MR in the absence of 11 beta HSD2 and steroids in transiently expressing HEK-293 cells, the transcriptional activity of MR was not stimulated. In contrast, CDCA and DCA both inhibited 11 beta HSD2 with IC(50) values of 22 and 38 microm, respectively and caused cortisol-dependent nuclear translocation and increased transcriptional activity of MR. LCA, the bile acid that most efficiently inhibited 11 beta HSD2, 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 11 beta HSD2, 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.
Stauffer
Anita T
AT
Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, 3010 Berne, Switzerland.
Rochat
Mascha K
MK
Dick
Bernhard
B
Frey
Felix J
FJ
Odermatt
Alex
A
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001647:Bile Acids and Salts / Q000652:urine; D016466:CHO Cells; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D002779:Cholestasis / Q000652:urine; D006224:Cricetinae; D003840:Deoxycholic Acid / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D042882:Gallstones / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D008956:Models, Chemical; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects*
D001647:Bile Acids and Salts; D018161:Receptors, Mineralocorticoid; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D006854:Hydrocortisone