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Title: Hepatic 5α-reduced glucocorticoids : modulators of glucocorticoid receptor activation in obesity
Author: McInnes, Kerry J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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In obese versus lean Zucker rats, hepatic 5α-reductase type 1 mRNA expression and protein levels were increased. They also had increased activity of hepatic 5β-reductase activity. By contrast, 3α-hydroxysteroid dehydrogenase mRNA expression was unchanged in obesity. Greater inactivation of B by A-ring reductases in liver may decrease local corticosterone (B) concentrations in these sites, and increase the metabolic clearance rate of glucocorticoids, thus increasing drive to the hypothalamic-pituitary-adrenal axis (HPA). To investigate whether 5α-reduced metabolites of corticosterone are glucocorticoid receptor agonists, competition binding studies were carried out. In displacing tritiated dexamethasone from binding sites in hepatocytes from male lean Zucker rats, B and 5α-tetrahydrocorticosterone (5αTHB) had similar affinities which were greater than 5α-dihydrocorticosterone (5αDHB) and 5β-reduced metabolites. Binding of B and 5αDHB binding was impaired in obesity whereas 5αTHB binding was unaltered suggesting that 5αTHB may modulate GR activation in obesity. Activation of flucocorticoid receptors was assessed following transient transfection into HeLa cells with an MMTV-luciferase reporter. By comparison with corticosterone, 5αTHB was active and additive. 5β-Reduced metabolites did not activate glucocorticoid receptors. In addition, in H4IIe cells which express endogenous glucocorticoid receptors, 5αTHB induced tyrosine aminotransferase mRNA expression albeit to a lesser extent than corticosterone. 5αTHB was also found to possess glucocorticoid activity in vivo as suppression of plasma ACTH was demonstrated in adrenalectomised lean Zucker rats following i.p. administration of B or 5αTHB. We conclude that hepatic A-ring reduction is enhanced in the obese Zucker rat producing increased concentrations of 5αTHB. Transcription of glucocorticoid regulated genes in tissues which express 5α-reductases will thus be influenced by intracellular levels of both corticosterone and its 5α-reduced metabolites. Manipulation of this enzyme may prove to be a useful therapeutic target in obesity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available