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Title: The impact of bile acids on glucocorticoid metabolism
Author: McNeilly, A. D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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The work in this thesis demonstrates that bile acids and their conjugates are competitive inhibitors of glucocorticoid metabolism by both 11β-HSD1 and 5β-reductase in liver. In vivo, in male Wistar rats, manipulation of hepatic bile acid concentrations by dietary supplementation with chenodeoxycholic acid (CDCA; 1% w/w) suppressed activities of hepatic 5β-reductase and 11βHSD1 activity and caused a reduction in total urinary (mainly 5β-reduced) glucocorticoid metabolites. In response to acute restraint stress bile acid treated animals showed a delay in return to basal corticosterone levels indicative of altered clearance. In addition, adrenal weight and lipid accumulation within the adrenal gland was reduced in bile acid treated animals. Stimulation of bile acid synthesis by cholestyramine (5% w/w) reduced hepatic 5β-reductase activity with animals excreting fewer urinary total (mainly 5β-reduced) glucocorticoid metabolites. Conversely, a reduction in hepatic bile acid content via administration of a fat-free diet, induced hepatic 5β-reductase activity accompanied by an increase in total, principally 5β-reduced, urinary metabolites. Animals fed the fat-free diet had larger adrenal glands, and suppressed circulating corticosterone, again suggesting altered HPA axis regulation. These findings were pursued in rats with bile duct ligation, a pathological model of elevated bile acids. In these animals, reduced activities of 5β-reductase and 11β-HSD1 were also identified. Lastly investigations were made of the impact of bile acids on the renin-angiotensin-aldosterone system (RAAS). Manipulations which increased bile acids concentrations were predicted to reduce the rate of aldosterone inactivation, since it too is a substrate for 5β-reductase. Treatments increasing bile acids were accompanied by a renin-independent increase in aldosterone and associated sodium retention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available