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

In vitro, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11 beta-HSD-1 is highly expressed in liver, where the reaction direction is 11 beta-reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11 beta-HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11 beta-HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions. We have selectively repressed hepatic 11 beta-HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11 beta-HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting 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 beta-HSD-1. These data suggest 11 beta-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.