The role of glucocorticoid metabolism in bile acid homeostasis

Abstract

Background and aims: Bile acids are conserved through enterohepatic circulation, a glucocorticoid-modulated process. 11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts cortisone/11-dehydrocortisone to cortisol/corticosterone, thus increasing intracellular glucocorticoid levels. 11β-HSD1 also metabolises 7-oxo-lithocholic acid, a bile acid. 11β-HSD1 is highly expressed in the liver and may alter bile acid transport through regeneration of active glucocorticoids or may directly metabolise bile acids, thus altering profile. We compared bile acid synthesis, release, their enterohepatic circulation and profile in Hsd11b1−/− and isogenic C57Bl/6 control mice. Methods: Adult male, chow-fed mice (eight per group) were fasted for 4 h or fasted for 4 h then re-fed 4 h. Serum, and liver and gall-bladder bile acid concentrations and profiles were measured by spectrophotometry/gas chromatography–mass spectrometry. Results: Fasted Hsd11b1−/− and C57Bl/6 mice had similar volumes of bile (3.2 vs 5.0 l). 7β-Hydroxylated acids (ω-muricholic>β-muricholic>ursodeoxycholic acid>others) predominated in bile of C57Bl/6 mice while 7α-hydroxylated acids (cholic>α-muricholic>chenodeoxycholic acid>others) predominated in Hsd11b1−/− mice; the ratio of 7α:7β acids was >100 greater in Hsd11b1−/−mice. In fasted Hsd11b1− mice, bile acid concentrations were higher in serum (Hsd11b1−/−: 30±9 vs C57Bl/6: 3.8±1.3 nM, P<0.0001) and liver (Hsd11b1−/−: 243±18 vs C57Bl/6: 139±19 nmol/g, P<0.001). Re-feeding caused gall bladder emptying in C57Bl/6 mice (49.6±8% of fasted weight, P<0.0001) and increased serum (62.5±7.6 nM) and liver (497±20 nmol/g) bile acid concentrations, while in Hsd11b1− mice, the gall bladder did not empty (92±7.8% fasted weight) and serum (24±12 nM) and liver (122±21 nmol/g) bile acid concentrations were similar to the fasted state. Conclusion: Bile acid release and the pattern of synthesis is controlled by 11β-HSD1 activity in mice. This may affect digestion and, depending on functional differences of 7α- and 7β- hydroxylated bile acids, may have significant effects on lipid and sterol metabolism and bile acid-mediated transcription.