CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11beta-hydroxysteroid dehydrogenase encoding gene in adipose cells.
Android obesity is often associated with a metabolic syndrome characterized, in particular, by a type 2 diabetes and cardiovascular problems. This could be induced by an excess of local production of glucocorticoids (GC) by adipose tissue (or other tissues). This production of GC by its target tissues depends on the 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) enzyme. Our aim was to characterize some mechanisms which control the expression of the human 11betaHSD1 gene (hHSD11B1) in preadipocytes. By using different luciferase constructs containing fragments of the hHSD11B1 promoter, we demonstrate that two members of the CCAAT/enhancer-binding protein family, C/EBPalpha and C/EBPbeta, are required for the basal transcriptional activity of HSD11B1 in 3T3-L1 preadipocyte cells. This effect depends on the binding of each isoform to specific binding sites. Mutation of either one of these sites induced a 40-50% decrease of the constitutive activity of the hHSD11B1 promoter. A forskolin treatment of 3T3-L1 preadipocyte cells induced an increased endogenous expression of HSD11B1. By transfection studies using the hHSD11B1 luciferase constructs, it appears that C/EBPbeta was strongly involved in this induction, as the forskolin stimulation was suppressed after mutation of the C/EBPbeta binding site. Part of the mechanism involved the increase of nuclear C/EBPbeta protein levels induced by forskolin and a phosphorylation step associated with an enhanced binding of the transcription factor to its site. These data indicate that members of the C/EBP family control intracellular levels of GC in preadipocytes via the regulation of the constitutive and cAMP-dependent expressions of HSD11B1.
Gout
Johann
J
Inserm, U449-Inra UMR 1235, faculté de médecine Laennec, 8, rue Guillaume-Paradin, 69372 Lyon, cedex 08, France.
Tirard
Julien
J
Thévenon
Chantal
C
Riou
Jean-Paul
JP
Bégeot
Martine
M
Naville
Danielle
D
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D016415:Sequence Alignment; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D020033:Protein Isoforms; D000242:Cyclic AMP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1