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

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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	705-711
Number of pages	7
Journal	Journal of Hepatology
Volume	52
Issue number	5
DOIs	https://doi.org/10.1016/j.jhep.2009.10.037
Publication status	Published - May 2010

Keywords / Materials (for Non-textual outputs)

Bile acid
Glucocorticoid
5β-reductase
Adrenal
Jaundice

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10.1016/j.jhep.2009.10.037

Bile acids modulate glucocorticoid metabolism and the hypothalamic–pituitary–adrenal axis in obstructive jaundice
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McNeilly, A. D., Macfarlane, D. P., O'Flaherty, E., Livingstone, D. E., Mitić, T., McConnell, K. M., McKenzie, S. M., Davies, E., Reynolds, R. M., Thiesson, H. C., Skøtt, O., Walker, B. R., & Andrew, R. (2010). Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice. Journal of Hepatology, 52(5), 705-711. https://doi.org/10.1016/j.jhep.2009.10.037

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title = "Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice",

abstract = "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.",

keywords = "Bile acid , Glucocorticoid , 5β-reductase , Adrenal , Jaundice ",

author = "McNeilly, {Alison D} and Macfarlane, {David P} and Emmett O'Flaherty and Livingstone, {Dawn E} and Tijana Miti{\'c} and McConnell, {Kirsty M} and McKenzie, {Scott M} and Eleanor Davies and Reynolds, {Rebecca M} and Thiesson, {Helle C} and Ole Sk{\o}tt and Walker, {Brian R} and Ruth Andrew",

year = "2010",

month = may,

doi = "10.1016/j.jhep.2009.10.037",

language = "English",

volume = "52",

pages = "705--711",

journal = "Journal of Hepatology",

issn = "0168-8278",

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McNeilly, AD, Macfarlane, DP, O'Flaherty, E, Livingstone, DE, Mitić, T, McConnell, KM, McKenzie, SM, Davies, E, Reynolds, RM, Thiesson, HC, Skøtt, O, Walker, BR & Andrew, R 2010, 'Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice', Journal of Hepatology, vol. 52, no. 5, pp. 705-711. https://doi.org/10.1016/j.jhep.2009.10.037

TY - JOUR

T1 - Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice

AU - McNeilly, Alison D

AU - Macfarlane, David P

AU - O'Flaherty, Emmett

AU - Livingstone, Dawn E

AU - Mitić, Tijana

AU - McConnell, Kirsty M

AU - McKenzie, Scott M

AU - Davies, Eleanor

AU - Reynolds, Rebecca M

AU - Thiesson, Helle C

AU - Skøtt, Ole

AU - Walker, Brian R

AU - Andrew, Ruth

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

KW - Bile acid

KW - Glucocorticoid

KW - 5β-reductase

KW - Adrenal

KW - Jaundice

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U2 - 10.1016/j.jhep.2009.10.037

DO - 10.1016/j.jhep.2009.10.037

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SN - 0168-8278

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EP - 711

JO - Journal of Hepatology

JF - Journal of Hepatology

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ER -

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

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