A novel promoter for the 11beta-hydroxysteroid dehydrogenase type 1 gene is active in lung and is C/EBPalpha independent.
11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) increases intracellular glucocorticoid action by converting inactive to active glucocorticoids (cortisol, corticosterone) within cells. It is highly expressed in glucocorticoid target tissues including liver and lung, and at modest levels in adipose tissue and brain. A selective increase in adipose 11beta-HSD1 expression occurs in obese humans and rodents and is likely to be of pathogenic importance in the metabolic syndrome. Here we have used 5' rapid amplificaiton of cDNA ends (RACE) to identify a novel promoter, P1, of the gene encoding 11beta-HSD1. P1 is located 23 kb 5' to the previously described promoter, P2. Both promoters are active in liver, lung, adipose tissue, and brain. However, P1 (encoding exon 1A) predominates in lung and P2 (encoding exon 1B) predominates in liver, adipose tissue, and brain. Adipose tissue of obese leptin-deficient C57BL/6J-Lepob mice showed higher expression only of the P2-associated exon 1B-containing 11beta-HSD1 mRNA variant. In contrast to P2, which is CAAAT/enhancer binding protein (C/EBP)-alpha inducible in transiently transfected cells, the P1 promoter was unaffected by C/EBPalpha in transfected cells. Consistent with these findings, mice lacking C/EBPalpha had normal 11beta-HSD1 mRNA levels in lung but showed a dramatic reduction in levels of 11beta-HSD1 mRNA in liver and brown adipose tissue. These results therefore demonstrate tissue-specific differential regulation of 11beta-HSD1 mRNA through alternate promoter usage and suggest that increased adipose 11beta-HSD1 expression in obesity is due to a selective increase in activity of the C/EBPalpha-regulated P2 promoter.
Endocrinology Unit, Centre for Cardiovascular Sciences, Queen's Institute for Medical Research, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
Charlotte
C
Bruley
Val
V
Lyons
Alan G F
AG
Worsley
Margaret D
MD
Wilde
Gretchen D
GD
Darlington
Nik M
NM
Morton
Jonathan R
JR
Seckl
Karen E
KE
Chapman
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D022763:CCAAT-Enhancer-Binding Protein-alpha; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1