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Endocrinology Vol. 142, No. 4 1371-1376
Copyright © 2001 by The Endocrine Society

ARTICLES

Minireview: 11ß-Hydroxysteroid Dehydrogenase Type 1— A Tissue-Specific Amplifier of Glucocorticoid Action1

Jonathan R. Seckl and Brian R. Walker

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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 J. Clin. Endocrinol. Metab.Home page
E. E. Kershaw and J. S. Flier
Adipose Tissue as an Endocrine Organ
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2548 - 2556.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. J. McInnes, C. J. Kenyon, K. E. Chapman, D. E. W. Livingstone, L. J. Macdonald, B. R. Walker, and R. Andrew
5{alpha}-Reduced Glucocorticoids, Novel Endogenous Activators of the Glucocorticoid Receptor
J. Biol. Chem., May 28, 2004; 279(22): 22908 - 22912.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. M. Paterson, N. M. Morton, C. Fievet, C. J. Kenyon, M. C. Holmes, B. Staels, J. R. Seckl, and J. J. Mullins
Metabolic syndrome without obesity: Hepatic overexpression of 11{beta}-hydroxysteroid dehydrogenase type 1 in transgenic mice
PNAS, May 4, 2004; 101(18): 7088 - 7093.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
T. C. Sandeep, J. L. W. Yau, A. M. J. MacLullich, J. Noble, I. J. Deary, B. R. Walker, and J. R. Seckl
From The Cover: 11{beta}-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics
PNAS, April 27, 2004; 101(17): 6734 - 6739.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
M. Duclos, C. Gouarne, C. Martin, C. Rocher, P. Mormede, and T. Letellier
Effects of corticosterone on muscle mitochondria identifying different sensitivity to glucocorticoids in Lewis and Fischer rats
Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E159 - E167.
[Abstract] [Full Text] [PDF]

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 Recent Prog Horm ResHome page
J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker
Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue
Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
T. Tsilchorozidou, J. W. Honour, and G. S. Conway
Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5{alpha}-Reduction But Not the Elevated Adrenal Steroid Production Rates
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5907 - 5913.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
K. Sun and L. Myatt
Enhancement of Glucocorticoid-Induced 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression by Proinflammatory Cytokines in Cultured Human Amnion Fibroblasts
Endocrinology, December 1, 2003; 144(12): 5568 - 5577.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
H.G. Klemcke, R. Sampath Kumar, K. Yang, J.L. Vallet, and R.K. Christenson
11{beta}-Hydroxysteroid Dehydrogenase and Glucocorticoid Receptor Messenger RNA Expression in Porcine Placentae: Effects of Stage of Gestation, Breed, and Uterine Environment
Biol Reprod, December 1, 2003; 69(6): 1945 - 1950.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
C. Christy, P. W.F. Hadoke, J. M. Paterson, J. J. Mullins, J. R. Seckl, and B. R. Walker
11{beta}-Hydroxysteroid Dehydrogenase Type 2 in Mouse Aorta: Localization and Influence on Response to Glucocorticoids
Hypertension, October 1, 2003; 42(4): 580 - 587.
[Abstract] [Full Text] [PDF]

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 Am. J. PsychiatryHome page
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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 J. Clin. Endocrinol. Metab.Home page
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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 Hum ReprodHome page
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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 EndocrinologyHome page
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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 EndocrinologyHome page
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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 ANN INTERN MEDHome page
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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 J. Clin. Endocrinol. Metab.Home page
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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 EndocrinologyHome page
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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 DiabetesHome page
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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 Am. J. Respir. Crit. Care Med.Home page
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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 J. Pharmacol. Exp. Ther.Home page
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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 Physiol. GenomicsHome page
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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 J. Biol. Chem.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 Biol. Reprod.Home page
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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 DiabetesHome page
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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 J. Clin. Endocrinol. Metab.Home page
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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 J. Clin. Endocrinol. Metab.Home page
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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 Adv. Physiol. Educ.Home page
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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 EndocrinologyHome page
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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 ScienceHome page
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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 CirculationHome page
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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