Tissue- and temporal-specific regulation of 11beta-hydroxysteroid dehydrogenase type 1 by glucocorticoids in vivo.
11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. Short-term glucocorticoid excess upregulates 11beta-HSD-1 in liver and hippocampus leading to suggestions that 11beta-HSD-1 ameliorates the deleterious effects of glucocorticoid excess by its 11beta-dehydrogenase activity. However the predominant activity of 11beta-HSD-1 in vivo is 11beta-reduction, thus generating active glucocorticoid. We have re-examined the time-course of glucocorticoid regulation of 11beta-HSD-1 in the liver, hippocampus and kidney of adult male rats in vivo. Sham operation markedly reduced 11beta-HSD-1 mRNA expression in all tissues, and reduced 11beta-HSD bioactivity in liver and hippocampus when compared to untouched controls. Adrenalectomy reduced 11beta-HSD-1 expression in all tissues in the short-term (7 days), followed by subsequent recovery of enzyme activity by 21 days in liver and hippocampus. Dexamethasone replacement of adrenalectomised rats attenuated the initial decrease in hepatic 11beta-HSD-1 activity, but by 21 days dexamethasone reduced activity compared to control levels. Thus glucocorticoids regulate 11beta-HSD-1 in a complex tissue- and temporal-specific manner. This pattern of regulation suggests glucocorticoids repress 11beta-HSD-1 at least in the liver, a pattern of regulation more consistent with the evidence that 11beta-HSD-1 is an 11beta-reductase in vivo. Operational stress per se down-regulates 11beta-HSD-1 which has implications for interpretation and design of in vivo studies of 11beta-HSD-1.
Molecular Endocrinology, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Scotland, UK. pjam@srv0.med.ed.ac.uk
P M
PM
Jamieson
K E
KE
Chapman
J R
JR
Seckl
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000315:Adrenalectomy; D000818:Animals; D004790:Enzyme Induction; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D005938:Glucocorticoids; D012333:RNA, Messenger; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases