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.
In vitro, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD-1 is highly expressed in liver, where the reaction direction is 11beta-reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11beta-HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11beta-HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions. We have selectively repressed hepatic 11beta-HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11beta-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 11beta-HSD-1. These data suggest 11beta-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.
Jamieson
P M
PM
Molecular Endocrinology, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
Nyirenda
M J
MJ
Walker
B R
BR
Chapman
K E
KE
Seckl
J R
JR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000315:Adrenalectomy; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D003345:Corticosterone / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009919:Orchiectomy; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D012333:RNA, Messenger; D004958:Estradiol; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D003345:Corticosterone