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

McNeilly, A. D. et al. (2010) Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice. Journal of Hepatology, 52(5), pp. 705-711. (doi:10.1016/j.jhep.2009.10.037)

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Publisher's URL: http://dx.doi.org/10.1016/j.jhep.2009.10.037

Abstract

<b>Background & Aims</b> 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.<p></p> <b>Methods</b> 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.<p></p> <b>Results</b> In 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).<p></p> 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.<p></p> In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-tetrahydrocortisol was significantly lower than in healthy controls.<p></p> <b>Conclusion</b> 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.<p></p>

Item Type:Articles
Keywords:11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 5 beta-reductase Adrenal adrenal insufficiency ASSOCIATION Bile acid CELLS CHENODEOXYCHOLIC ACID CIRRHOSIS Corticosterone diabetes Diet DISEASE GENE GENE-EXPRESSION Glucocorticoid HepG2 Human HUMANS IN-VITRO IN-VIVO Jaundice LEVEL LIVER Metabolism MINERALOCORTICOID RECEPTOR OBESE ZUCKER RATS RAT RATS Scotland SEPTIC SHOCK SUPPLEMENTATION SUPPRESSION SYSTEM TISSUE UNIT weight WOMEN
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Andrew, Dr Ruth and Davies, Professor Eleanor and MacKenzie, Dr Scott and Walker, Dr Brian
Authors: McNeilly, A. D., Macfarlane, D. P., O'Flaherty, E., Livingstone, D. E., Mitic, T., McConnell, K. M., MacKenzie, S. M., Davies, E., Reynolds, R. M., Thiesson, H. C., Skott, O., Walker, B. R., and Andrew, R.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hepatology
Publisher:Elsevier BV
ISSN:0168-8278
ISSN (Online):1600-0641
Published Online:04 March 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences