Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The VSports app下载. gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2010 May;52(5):705-11.
doi: 10.1016/j.jhep.2009.10.037. Epub 2010 Mar 4.

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

Alison D McNeilly  1 , 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
Affiliations

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

Alison D McNeilly et al. J Hepatol. 2010 May.

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 5beta-reductase VSports手机版. .

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 5beta-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. V体育安卓版.

Results: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5beta-reductase (K(i) 9. 19+/-0. 40 microM) 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 5beta-reductase activity, reduced urinary excretion of 3alpha,5beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5beta-reductase activity, and urinary 3alpha,5beta-reduced corticosterone V体育ios版. Cholestasis in rats suppressed hepatic 5beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3alpha,5beta-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 VSports最新版本. .

PubMed Disclaimer

Figures (VSports注册入口)

Fig. 1
Fig. 1
Inhibition of 5β-reductase by bile acids. 5β-Reduction of corticosterone in the presence of (A) CDCA, CA, DCA (B) CDCA, GCDCA, TCDCA. Velocity vs. Control (100%), without bile acids. (C) IC50 of the reactions. (D) Lineweaver–Burke plots showing competitive inhibition of 5β-reductase by CDCA (open squares: 2.5 × 10–6 M) (vs. vehicle (filled)). Mean ± SEM; n = 5. ∗p <0.05 vs. CDCA; #p <0.05 DCA vs. CA.
Fig. 2
Fig. 2
Effect of CDCA on transcription of steroid-metabolising enzymes. (A) Abundance of mRNAs of rat 5β-reductase and Cyp7a1 but not 3αHSD was suppressed in H4iiE cells by CDCA (100 μM), n = 5. (B) Activity of the promoter of human 5β-reductase was reduced by CDCA (50 μM). Data are fold induction of luciferase activity relative to control plasmid. (n = 3 triplicates), mean ± SEM; ∗p <0.05, ∗∗∗p <0.001 vs. vehicle.
Fig. 3
Fig. 3
In vivoelevation of bile acids inhibits hepatic 5β-reductase in rats. (A) Hepatic 5β-reductase activity was inhibited in rats following dietary CDCA (filled) vs. Control (open) and (B) following BDL (filled) vs. sham operation (open). Mean ± SEM; ∗p <0.05 vs. Control, #p <0.05 vs. Fat-free (FF) diet, ∗∗∗p <0.001 vs. Sham.
Fig. 4
Fig. 4
Dietary CDCA delays recovery from acute stress in rats. Following restraint (hatched), animals treated with CDCA (filled) had a delay in the return to basal levels of corticosterone (A) but not ACTH (B), compared to Controls (open). Mean ± SEM; ∗p <0.05 vs. Control.
See this image and copyright information in PMC

References

    1. Harry R., Auzinger G., Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology. 2002;36:395–402. - VSports注册入口 - PubMed
    1. Tsai M.H., Peng Y.S., Chen Y.C., Liu N.J., Ho Y.P., Fang J.T. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006;43:673–681. - PubMed
    1. Fernandez J., Escorsell A., Zabalza M., Felipe V., Navasa M., Mas A. Adrenal insufficiency in patients with cirrhosis and septic shock. Hepatology. 2006;44:1288–1295. - PubMed
    1. Swain M.G., Patchev V., Vergalla J., Chrousos G., Jones E.A. Suppression of hypothalamic–pituitary–adrenal axis responsiveness to stress in a rat model of acute cholestasis. J Clin Invest. 1993;91:1903–1908. - PMC - PubMed
    1. Demelia L., Solinas A., Poma R., Vallebona E., Pitzus F. Hypothalamo–pituitary–adrenal function in liver cirrhosis of viral etiology. Ann Ital Med Int. 1991;6:203–209. - PubMed

VSports在线直播 - Publication types

MeSH terms

"V体育安卓版" Substances