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A Novel Promoter for the 11ß-Hydroxysteroid Dehydrogenase Type 1 Gene Is Active in Lung and Is C/EBP Independent

Endocrinology Unit (C.B., V.L., A.G.F.W., N.M.M., J.R.S., K.E.C.), Centre for Cardiovascular Sciences, Queen’s Institute for Medical Research, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; and Huffington Center on Aging (M.D.W., G.D.D.), N805, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Karen E. Chapman, Endocrinology Unit, Centre for Cardiovascular Sciences, Queen’s Institute for Medical Research, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: Karen.Chapman{at}ed.ac.uk.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-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 11ß-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-Lep^ob mice showed higher expression only of the P2-associated exon 1B-containing 11ß-HSD1 mRNA variant. In contrast to P2, which is CAAAT/enhancer binding protein (C/EBP)- inducible in transiently transfected cells, the P1 promoter was unaffected by C/EBP in transfected cells. Consistent with these findings, mice lacking C/EBP had normal 11ß-HSD1 mRNA levels in lung but showed a dramatic reduction in levels of 11ß-HSD1 mRNA in liver and brown adipose tissue. These results therefore demonstrate tissue-specific differential regulation of 11ß-HSD1 mRNA through alternate promoter usage and suggest that increased adipose 11ß-HSD1 expression in obesity is due to a selective increase in activity of the C/EBP-regulated P2 promoter.

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				S. Sai, C. L. Esteves, V. Kelly, Z. Michailidou, K. Anderson, A. P. Coll, Y. Nakagawa, T. Ohzeki, J. R. Seckl, and K. E. Chapman Glucocorticoid Regulation of the Promoter of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Is Indirect and Requires CCAAT/Enhancer-Binding Protein-{beta} Mol. Endocrinol., September 1, 2008; 22(9): 2049 - 2060. [Abstract] [Full Text] [PDF]