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 5β-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 5β-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 5β-reductase (K_i 9.19±0.40μM) 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 5β-reductase activity, reduced urinary excretion of 3α,5β-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5β-reductase activity, supplementation of the fat-free diet with CDCA reduced 5β-reductase activity, and urinary 3α,5β-reduced corticosterone. Cholestasis in rats suppressed hepatic 5β-reductase activity and transcript abundance.

In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-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.

Abbreviations: HPA, hypothalamic–pituitary–adrenal, ACTH, adrenocorticotropic hormone, 3αHSD, 3α-hydroxysteroid dehydrogenase, FXR, farnesoid X receptor, Cyp7a1, cholesterol 7α-hydroxylase, 11βHSD, 11β-hydroxysteroid dehydrogenase, BDL, bile duct ligation, THB, tetrahydrocorticosterone, DHB, dihydrocorticosterone, GCMS, gas chromatography mass spectrometry, CDCA, chenodeoxycholic acid, CA, cholic acid, DCA, deoxycholic acid, GCDCA, glyco-CDCA, K_i, inhibitor constant, TCDCA, tauro-CDCA, DMEM, Dulbecco’s modified Eagle’s medium, PCR, polymerase chain reaction, FF, fat-free, ECRP, endoscopic retrograde cholangiopancreatography, ANOVA, analysis of variance, ALT, alanine transaminase, ALP, alkaline phosphatase, Cyp11b1, 11β-hydroxylase, NEFA, non-esterified fatty acids, SEM, standard error of mean

Keywords: Bile acid, Glucocorticoid, 5β-reductase, Adrenal, Jaundice