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Title: The role and regulation of hepatic 11β-hydroxysteroid dehydrogenase type 1
Author: Jamieson, Pauline Margaret
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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The purpose of this thesis was to investigate the regulation and function of 11β-HSD-1 in liver and in the hippocampus. Examination of 11β-HSD-1 activity in a liver perfusion system by measurement of glucocorticoid metabolism across the intact liver confirmed that 11β-reduction is the predominant reaction in this organ and indicated that the route of delivery of substrate is important, with the reactivation of inert substrate increasing as the ratio perfused through the hepatic portal vein: hepatic artery increases. These data suggest that hepatic 11β-HSD-1 activity in liver potentially increases intrahepatic active glucocorticoid levels. Many hepatic enzymes of carbohydrate and fat metabolism are regulated by glucocorticoids, including phosphoenol carboxykinase (PEPCK), the rate-limiting enzyme gluconeogenesis and in humans, 11β-HSD inhibition increases hepatic insulin sensitivity. Therefore I examined the effect of selective and near complete repression of hepatic- 11β-HSD-1 by oestradiol on glucocorticoid-inducible gene expression in liver. Oestradiol treatment resulted in reduced expression of glucocorticoid-inducible genes, including PEPCK. This effect could not be attributed to a direct action of oestradiol. Furthermore, inhibition of whole body 11β-HSD-1 plays an important role in potentiating glucocorticoid action in the liver and illustrates the potential to alter gluconeogenesis/insulin sensitivity by manipulating hepatic 11β-HSD-1 activity. Examination of the regulation of hippocampal 11β-HSD-1 demonstrated that intracerebroventricular administration of growth hormone had no effect on 11β-HSD mRNA expression. This is in direct contrast the periphery, where growth hormone is a major regulator. Examination of 11β-HSD-1 activity in the hippocampus and liver in a well-documented model of chronic psychosocial stress in the tree-shrew showed that chronic stress attenuates hippocampal 11β-HSD-1 activity, whereas excess glucocorticoid administration has no effect.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available