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

Alison D Mcneilly,David P Macfarlane,Emmett O’Flaherty,Dawn E Livingstone,Tijana Mitić,Kirsty M Mcconnell,Scott M Mckenzie,Eleanor Davies,Rebecca M Reynolds,Helle C Thiesson,Ole Skøtt,Brian R Walker,Ruth Andrew

doi:10.1016/j.jhep.2009.10.037

Abstract

Background & AimsSuppression 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.MethodsThe 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.ResultsIn rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5β-reductase (Ki 9.19 ± 0.40 μM) 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.ConclusionThese 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.

Highlights

Activation of the hypothalamic–pituitary–adrenal (HPA) axis and enhanced release of cortisol is crucial to a successful response to stress, but this homeostatic mechanism is disrupted in liver disease
This study shows that bile acids, CDCA, are potent competitive and transcriptional inhibitors of rat hepatic 5breductase in vitro
5b-reductase activity was increased by feeding rats an FF diet, and this effect was reversed by CDCA supplementation

Summary

Introduction

Activation of the hypothalamic–pituitary–adrenal (HPA) axis and enhanced release of cortisol is crucial to a successful response to stress, but this homeostatic mechanism is disrupted in liver disease. If metabolism of cortisol is impaired, negative feedback control of the HPA axis causes suppression of ACTH levels, atrophy of the adrenal gland and a reduced rate of production of cortisol, a pattern seen in cirrhosis [5,6]. Inhibition of renal 11bHSD2 by bile acids impairs glucocorticoid inactivation [10,11] and contributes to the sodium retention and potassium wasting observed in cirrhosis and cholestasis [12] as well as following bile duct ligation (BDL) [13], through illicit occupation of mineralocorticoid receptors by excess cortisol. We hypothesised that bile acid accumulation in cholestasis inhibits hepatic 5b- reductase, contributing to impaired glucocorticoid clearance and attenuation of HPA axis activity. Glucocorticoid metabolism was studied in humans following obstruction of the common bile duct by gallstones

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