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Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom
Address all correspondence and requests for reprints to: Professor Jonathan R. Seckl, Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. E-mail: J.Seckl{at}ed.ac.uk
11ß-hydroxysteroid dehydrogenases (11ß-HSDs) catalyze the interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11ß-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11ß-HSD type 1 has, until recently, been little understood. 11ß-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11ß-HSD1 acts as a predominant 11ß-reductase in many intact cells, whole organs, and in vivo. This reaction direction locally regenerates active glucocorticoids within expressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reaction direction are not fully understood, insights to its biological importance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11ß-HSD1 effectively amplifies glucocorticoid action at least in the liver, adipose tissue, and the brain. Inhibition of 11ß-HSD1 represents a potential target for therapy of disorders that might be ameliorated by local reduction of glucocorticoid action, including type 2 diabetes, obesity, and age-related cognitive dysfunction.
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G. Banhegyi, A. Benedetti, R. Fulceri, and S. Senesi Cooperativity between 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-phosphate Dehydrogenase in the Lumen of the Endoplasmic Reticulum J. Biol. Chem., June 25, 2004; 279(26): 27017 - 27021. [Abstract] [Full Text] [PDF] |
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C. L. Raison and A. H. Miller When Not Enough Is Too Much: The Role of Insufficient Glucocorticoid Signaling in the Pathophysiology of Stress-Related Disorders Am J Psychiatry, September 1, 2003; 160(9): 1554 - 1565. [Abstract] [Full Text] [PDF] |
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D. J. Wake, E. Rask, D. E. W. Livingstone, S. Soderberg, T. Olsson, and B. R. Walker Local and Systemic Impact of Transcriptional Up-Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3983 - 3988. [Abstract] [Full Text] [PDF] |
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L.M. Thurston, D.P. Norgate, K.C. Jonas, L. Gregory, P.J. Wood, B.A. Cooke, and A.E. Michael Ovarian modulators of type 1 11{beta}-hydroxysteroid dehydrogenase (11{beta}HSD) activity and intra-follicular cortisol:cortisone ratios correlate with the clinical outcome of IVF Hum. Reprod., August 1, 2003; 18(8): 1603 - 1612. [Abstract] [Full Text] [PDF] |
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C. Mattsson, M. Lai, J. Noble, E. McKinney, J. L. Yau, J. R. Seckl, and B. R. Walker Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus--Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity Endocrinology, July 1, 2003; 144(7): 2997 - 3003. [Abstract] [Full Text] [PDF] |
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B. J. Waddell, S. Hisheh, Z. S. Krozowski, and P. J. Burton Localization of 11{beta}-Hydroxysteroid Dehydrogenase Types 1 and 2 in the Male Reproductive Tract Endocrinology, July 1, 2003; 144(7): 3101 - 3106. [Abstract] [Full Text] [PDF] |
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H. Raff and J. W. Findling A Physiologic Approach to Diagnosis of the Cushing Syndrome Ann Intern Med, June 17, 2003; 138(12): 980 - 991. [Full Text] [PDF] |
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R. S. Lindsay, D. J. Wake, S. Nair, J. Bunt, D. E. W. Livingstone, P. A. Permana, P. A. Tataranni, and B. R. Walker Subcutaneous Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity and Messenger Ribonucleic Acid Levels Are Associated with Adiposity and Insulinemia in Pima Indians and Caucasians J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2738 - 2744. [Abstract] [Full Text] [PDF] |
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M. Kusakabe, I. Nakamura, and G. Young 11{beta}-Hydroxysteroid Dehydrogenase Complementary Deoxyribonucleic Acid in Rainbow Trout: Cloning, Sites of Expression, and Seasonal Changes in Gonads Endocrinology, June 1, 2003; 144(6): 2534 - 2545. [Abstract] [Full Text] [PDF] |
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Y. Liu, Y. Nakagawa, Y. Wang, R. Li, X. Li, T. Ohzeki, and T. C. Friedman Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice Diabetes, June 1, 2003; 52(6): 1409 - 1416. [Abstract] [Full Text] [PDF] |
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S. Suzuki, K. Koyama, A. Darnel, H. Ishibashi, S. Kobayashi, H. Kubo, T. Suzuki, H. Sasano, and Z. S. Krozowski Dexamethasone Upregulates 11{beta}-Hydroxysteroid Dehydrogenase Type 2 in BEAS-2B Cells Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1244 - 1249. [Abstract] [Full Text] [PDF] |
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D. E. W. Livingstone and B. R. Walker Is 11beta -Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 167 - 172. [Abstract] [Full Text] |
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M. Liang, B. Yuan, E. Rute, A. S. Greene, M. Olivier, and A. W. Cowley Jr. Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression Physiol Genomics, February 6, 2003; 12(3): 229 - 237. [Abstract] [Full Text] [PDF] |
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N. Shafqat, B. Elleby, S. Svensson, J. Shafqat, H. Jornvall, L. Abrahmsen, and U. Oppermann Comparative Enzymology of 11beta -Hydroxysteroid Dehydrogenase Type 1 from Glucocorticoid Resistant (Guinea Pig) Versus Sensitive (Human) Species J. Biol. Chem., January 10, 2003; 278(3): 2030 - 2035. [Abstract] [Full Text] [PDF] |
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R. C. Andrews, O. Rooyackers, and B. R. Walker Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 285 - 291. [Abstract] [Full Text] [PDF] |
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E. Kajantie, L. Dunkel, U. Turpeinen, U.-H. Stenman, P. J. Wood, M. Nuutila, and S. Andersson Placental 11{beta}-Hydroxysteroid Dehydrogenase-2 and Fetal Cortisol/Cortisone Shuttle in Small Preterm Infants J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 493 - 500. [Abstract] [Full Text] [PDF] |
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R. C. Andrews, O. Herlihy, D. E. W. Livingstone, R. Andrew, and B. R. Walker Abnormal Cortisol Metabolism and Tissue Sensitivity to Cortisol in Patients with Glucose Intolerance J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5587 - 5593. [Abstract] [Full Text] [PDF] |
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K. Sun, P. He, and K. Yang Intracrine Induction of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression by Glucocorticoid Potentiates Prostaglandin Production in the Human Chorionic Trophoblast Biol Reprod, November 1, 2002; 67(5): 1450 - 1455. [Abstract] [Full Text] [PDF] |
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T. M. Stulnig, U. Oppermann, K. R. Steffensen, G. U. Schuster, and J.-A. Gustafsson Liver X Receptors Downregulate 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity Diabetes, August 1, 2002; 51(8): 2426 - 2433. [Abstract] [Full Text] [PDF] |
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E. Rask, B. R. Walker, S. Soderberg, D. E. W. Livingstone, M. Eliasson, O. Johnson, R. Andrew, and T. Olsson Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3330 - 3336. [Abstract] [Full Text] [PDF] |
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O. Paulmyer-Lacroix, S. Boullu, C. Oliver, M.-C. Alessi, and M. Grino Expression of the mRNA Coding for 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue from Obese Patients: An in Situ Hybridization Study J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2701 - 2705. [Abstract] [Full Text] [PDF] |
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R. E. Booth, J. P. Johnson, and J. D. Stockand ALDOSTERONE Advan Physiol Educ, March 1, 2002; 26(1): 8 - 20. [Abstract] [Full Text] [PDF] |
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G.-M. Wang, R.-S. Ge, S. A. Latif, D. J. Morris, and M. P. Hardy Expression of 11{beta}-Hydroxylase in Rat Leydig Cells Endocrinology, February 1, 2002; 143(2): 621 - 626. [Abstract] [Full Text] [PDF] |
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H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R. Seckl, and J. S. Flier A Transgenic Model of Visceral Obesity and the Metabolic Syndrome Science, December 7, 2001; 294(5549): 2166 - 2170. [Abstract] [Full Text] [PDF] |
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P. W.F. Hadoke, C. Christy, Y. V. Kotelevtsev, B. C. Williams, C. J. Kenyon, J. R. Seckl, J. J. Mullins, and B. R. Walker Endothelial Cell Dysfunction in Mice After Transgenic Knockout of Type 2, but Not Type 1, 11{beta}-Hydroxysteroid Dehydrogenase Circulation, December 4, 2001; 104(23): 2832 - 2837. [Abstract] [Full Text] [PDF] |
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