Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice

Background & Aims: Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5 beta-reductase. Methods: The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5 beta-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. Results: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5 beta-reductase (K(i) 9.19 +/- 0.40 mu M) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5 beta-reductase activity, reduced urinary excretion of 3 alpha,5 beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5 beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5 beta-reductase activity, and urinary 3 alpha,5 beta-reduced corticosterone. Cholestasis in rats suppressed hepatic 5 beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3 alpha,5 beta-tetrahydrocortisol was significantly lower than in healthy controls. Conclusion: These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic-pituitary-adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease. Crown copyright (C) 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. All rights reserved.