11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism.
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) is a key enzyme in glucocorticoid metabolism, catalysing the conversion of active glucocorticoids into their inactive 11-keto metabolites, thus regulating glucocorticoid access to intracellular receptors. The type 1 isoform (11 beta-HSD 1) (EC 1.1.1.146) is widely distributed, with particularly high levels in liver, where accumulating evidence suggests that it acts as an 11 beta-reductase, regenerating active glucocorticoids. Investigation of the function and regulation of 11 beta-HSD 1 in liver has been hampered by the lack of hepatic cell lines which express 11 beta-HSD 1. Here, we describe 11 beta-HSD 1 mRNA expression and activity in 2S FAZA cells, a continuously cultured rat liver cell line. In intact 2S FAZA cells 11 beta-HSD 1 acts predominantly as a reductase, with very low dehydrogenase activity. In 2S FAZA cells 11 beta-HSD 1 activity and mRNA expression are regulated by hormones, with dexamethasone increasing activity and insulin, forskolin and insulin-like growth factor 1 decreasing it. Transfection of 2S FAZA cells with a luciferase reporter gene driven by the proximal promoter of the rat 11 beta-HSD 1 gene demonstrates that sequences which can mediate the responses to insulin, dexamethasone and forskolin all lie within 1800 bp of the transcription start site.
Voice
M W
MW
Department of Medicine, Western General Hospital, University of Edinburgh, U.K.
Seckl
J R
JR
Edwards
C R
CR
Chapman
K E
KE
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D006528:Carcinoma, Hepatocellular; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008113:Liver Neoplasms; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
D005938:Glucocorticoids; D006728:Hormones; D007328:Insulin; D005576:Colforsin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases