Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11beta-hydroxysteroid dehydrogenase type 1

Abstract

In vitro, 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11 -HSD-1 is highly expressed in liver, where the reaction direction is 11 -reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11 -HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11 -HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions.We have selectively repressed hepatic 11 -HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11 -HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the ratelimiting step in gluconeogenesis. Similar effects were seen after 3 weeks of oestradiol treatment. To examine whether this was due to any direct effect of oestradiol upon PEPCK, the experiment was repeated in adrenalectomised rats glucocorticoid replacement. In adrenalectomised rats, oestradiol did not attenuate hepatic PEPCK, whilst glucocorticoid replacement restored this action. Oestradiol did not alter hepatic metabolism of corticosterone by pathways other than 11 -HSD-1.These data suggest 11 -HSD-1 plays an important role in maintaining expression of key glucocorticoid-regulated hepatic transcripts. Enzyme inhibition may provide a useful therapeutic target for manipulating glucose homeostasis.

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

“…Oestrogen treatment of ob/ob mice decreased the activity and expression of hepatic glucose-6-phosphatase, contributing to normalisation of blood glucose levels [27]. Furthermore, estrogen treatment of rats significantly decreased the hepatic activity and expression of 11β-hydroxysteroid dehydrogenase type 1, an enzyme that catalyses the conversion of inactive 11-dehydrocorticosterone to corticosterone [28].…”

Expression of 11β-hydroxysteroid dehydrogenase 1 and 2 in subcutaneous adipose tissue of lean and obese women with and without polycystic ovary syndrome

“…In the liver, the expression and activity of 11b-HSD1 is increased in male rats compared with female rats, 40 and estrogen treatment represses hepatic 11b-HSD1 mRNA expression and activity in rodents. 41,20 Whole-body 11b-reductase activity, which primarily reflects hepatic 11b-HSD1activity, is higher in men than in women, [42][43][44] suggesting a genderspecific regulation also in humans. Lean women have lower 11b-HSD1 expression in adipose tissue than lean men; however, this gender-specific difference disappears in obesity.…”

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

“…Glucocorticoids have been shown to oppose the actions of insulin in the liver by upregulating expression of the rate-limiting enzyme PEPCK (Low et al 1994). Oestradiol, only in the presence of glucocorticoids, also downregulates expression of PEPCK (Jamieson et al 1999). Morton et al (2001) and others have shown that 11 -HSD1-null mice have increased hepatic insulin sensitivity, and increased glycaemic control for similar insulin concentrations.…”

“…Fetal infusion of glucocorticoid and oestradiol have been found to stimulate 11 -HSD1 mRNA expression and enzyme activity (Wang et al 1997, Sloboda et al 2001. In contrast, other researchers reported that infusion of dexamethasone (a synthetic glucocorticoid) and oestradiol decreased hepatic 11 -HSD1 mRNA and reductase activity in the male rat (Jamieson et al 1999, Nwe et al 2000. Thus the separate effects of cortisol and oestradiol on hepatic 11 -HSD1 and GR in the late-gestation sheep fetus remain unclear.…”

“…During late pregnancy, fetal cortisol plays a major part in maturation of several fetal organ systems, including the lung, liver, kidneys and gut (Fowden et al 1998). In the fetal liver, glucocorticoids regulate hepatic functions, including lipid and carbohydrate metabolism (Silver 1990, Jamieson et al 1999. Cortisol reaches the liver from the systemic circulation, or may be produced locally under the influence of the enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD).…”