Skip to main content
SpringerLink
Log in

The Dehydrogenase Hypothesis

  • Chapter
Glucocorticoid Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 872))

Abstract

Circulating glucocorticoid (GC) levels are controlled by the Hypothalamo–Pituitary–Adrenal (HPA) axis, but within tissues, GC availability is controlled by the isoforms of 11β (Beta)-Hydroxysteroid Dehydrogenase 11β (Beta)-HSD that interconvert inactive cortisone and active cortisol. Two isoforms have been identified; in key metabolic target tissues (including liver and adipose), expression of 11β (Beta)-HSD1 predominates that in vivo converts cortisone to cortisol and thus amplifies local GC action. In contrast, in mineralocorticoid target tissues 11β (Beta)-HSD2 is the isoform that is most abundantly expressed. This inactivates cortisol to cortisone and offers protection for the mineralocorticoid receptor form occupation and activation by cortisol. Dysregulated 11β (Beta)-HSD1 activity has been implicated in many metabolic diseases such as obesity and diabetes and inhibition of 11β (Beta)-HSD1 represents a promising therapeutic target. Mutations within the gene encoding 11β (Beta)-HSD2 cause the Syndrome of Apparent Mineralocorticoid Excess and decreases in activity are linked to hypertension as well as impairment in placental function and neonatal growth. We will discuss the molecular biology and enzymology of 11β (Beta)-HSD and its role in normal physiology and discuss altered 11β (Beta)-HSD activity in pathological states and the potential for therapeutic targeting.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Munck A, Náray-Fejes-Tóth A. The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol Cell Endocrinol. 1992;90(1):C1–4. http://www.ncbi.nlm.nih.gov/pubmed/1301388. Accessed 31 Dec 2013.

  2. Anagnostis P, Katsiki N, Adamidou F, et al. 11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders? Metabolism. 2013;62(1):21–33. doi:10.1016/j.metabol.2012.05.002.

    CAS  PubMed  Google Scholar 

  3. Bujalska IL, Kumar SSP. Does central obesity reflect “Cushing’s disease of the omentum”? Lancet. 1997;349(9060):1210–3.

    CAS  PubMed  Google Scholar 

  4. Tomlinson JW, Sherlock M, Hughes B, et al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis. J Clin Endocrinol Metab. 2007;92(3):857–64. doi:10.1210/jc.2006-2325.

    CAS  PubMed  Google Scholar 

  5. Tomlinson JW, Moore JS, Clark PMS, Holder G, Shakespeare L, Stewart PM. Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J Clin Endocrinol Metab. 2004;89(6):2711–6. doi:10.1210/jc.2003-031376.

    CAS  PubMed  Google Scholar 

  6. Chapman K, Holmes M, Seckl J. 11β-Hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013;93(3):1139–206. doi:10.1152/physrev.00020.2012.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Tomlinson JW, Walker EA, Bujalska IJ, et al. 11Beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25(5):831–66. doi:10.1210/er.2003-0031.

    CAS  PubMed  Google Scholar 

  8. Feig PU, Shah S, Hermanowski-Vosatka A, et al. Effects of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes Metab. 2011;13(6):498–504. doi:10.1111/j.1463-1326.2011.01375.x.

    CAS  PubMed  Google Scholar 

  9. Edwards CR, Stewart PM, Burt D, et al. Localisation of 11 beta-hydroxysteroid dehydrogenase—tissue specific protector of the mineralocorticoid receptor. Lancet. 1988;2(8618):986–9. http://www.ncbi.nlm.nih.gov/pubmed/2902493. Accessed 23 Feb 2014.

  10. Esteban NV, Loughlin T, Yergey AL, et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab. 1991;72(1):39–45. doi:10.1210/jcem-72-1-39.

    CAS  PubMed  Google Scholar 

  11. Keenan DM, Roelfsema F, Veldhuis JD. Endogenous ACTH concentration-dependent drive of pulsatile cortisol secretion in the human. Am J Physiol Endocrinol Metab. 2004;287(4):E652–61. doi:10.1152/ajpendo.00167.2004.

    CAS  PubMed  Google Scholar 

  12. Siiteri PK, Murai JT, Hammond GL, Nisker JA, Raymoure WJ, Kuhn RW. The serum transport of steroid hormones. Recent Prog Horm Res. 1982;38:457–510. http://www.ncbi.nlm.nih.gov/pubmed/6750727. Accessed 30 Dec 2013.

  13. Dorin RI, Qiao Z, Qualls CR, Urban FK. Estimation of maximal cortisol secretion rate in healthy humans. J Clin Endocrinol Metab. 2012;97(4):1285–93. doi:10.1210/jc.2011-2227.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Toothaker RD, Welling PG. Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression. J Pharmacokinet Biopharm. 1982;10(2):147–56. http://www.ncbi.nlm.nih.gov/pubmed/7120045. Accessed 9 Feb 2014.

  15. Meulenberg PM, Hofman JA. Differences between concentrations of salivary cortisol and cortisone and of free cortisol and cortisone in plasma during pregnancy and postpartum. Clin Chem. 1990;36(1):70–5. http://www.ncbi.nlm.nih.gov/pubmed/2297937. Accessed 7 Mar 2014.

  16. Kendall EC. Cortisone: memoirs of a hormone hunter. New York: Charles Scribner’s Sons; 1971.

    Google Scholar 

  17. Hench PS, Kendall EC. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181–97. http://www.ncbi.nlm.nih.gov/pubmed/18118071.

    CAS  PubMed  Google Scholar 

  18. Burton RB, Keutmann EH, Waterhouse C, Schuler EA. The conversion of cortisone acetate to other alphaketolic steroids. J Clin Endocrinol Metab. 1953;13(1):48–63. doi:10.1210/jcem-13-1-48.

    CAS  PubMed  Google Scholar 

  19. Amelung D, Hubener HJ, Roka L, Meyerheim G. Conversion of cortisone to compound F. J Clin Endocrinol Metab. 1953;13(9):1125–6. doi:10.1210/jcem-13-9-1125.

    CAS  PubMed  Google Scholar 

  20. Kavanagh KL, Jörnvall H, Persson B, Oppermann U. Medium- and short-chain dehydrogenase/reductase gene and protein families: the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cell Mol Life Sci. 2008;65(24):3895–906. doi:10.1007/s00018-008-8588-y.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Agarwal AK, Monder C, Eckstein B, White PC. Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase. J Biol Chem. 1989;264(32):18939–43. http://www.ncbi.nlm.nih.gov/pubmed/2808402.

    CAS  PubMed  Google Scholar 

  22. Lakshmi V, Monder C. Purification and characterization of the corticosteroid 11 beta-dehydrogenase component of the rat liver 11 beta-hydroxysteroid dehydrogenase complex. Endocrinology. 1988;123(5):2390–8. doi:10.1210/endo-123-5-2390.

    CAS  PubMed  Google Scholar 

  23. Tannin GM, Agarwal AK, Monder C, New MI, White PC. The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J Biol Chem. 1991;266(25):16653–8.

    Google Scholar 

  24. Nobel CSI, Dunås F, Abrahmsén LB. Purification of full-length recombinant human and rat type 1 11beta-hydroxysteroid dehydrogenases with retained oxidoreductase activities. Protein Expr Purif. 2002;26(3):349–56. http://www.ncbi.nlm.nih.gov/pubmed/12460758. Accessed 5 Jan 2014.

  25. Maser E, Völker B, Friebertshäuser J. 11 Beta-hydroxysteroid dehydrogenase type 1 from human liver: dimerization and enzyme cooperativity support its postulated role as glucocorticoid reductase. Biochemistry. 2002;41(7):2459–65. http://www.ncbi.nlm.nih.gov/pubmed/11841241. Accessed 31 Dec 2013.

  26. Odermatt A. The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane. J Biol Chem. 1999;274(40):28762–70. doi:10.1074/jbc.274.40.28762.

    CAS  PubMed  Google Scholar 

  27. Bujalska IJ, Draper N, Michailidou Z, et al. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1. J Mol Endocrinol. 2005;34(3):675–84. doi:10.1677/jme.1.01718.

    CAS  PubMed  Google Scholar 

  28. Draper N, Walker EA, Bujalska IJ, et al. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet. 2003;34(4):434–9. doi:10.1038/ng1214.

    CAS  PubMed  Google Scholar 

  29. Murphy VE, Clifton VL. Alterations in human placental 11beta-hydroxysteroid dehydrogenase type 1 and 2 with gestational age and labour. Placenta. 2003;24(7):739–44. http://www.ncbi.nlm.nih.gov/pubmed/12852864. Accessed 12 Feb 2014.

  30. Jinno K, Sakura N, Nomura S, Fujitaka M, Ueda K, Kihara M. Failure of cortisone acetate therapy in 21-hydroxylase deficiency in early infancy. Pediatr Int. 2001;43(5):478–82. http://www.ncbi.nlm.nih.gov/pubmed/11737708. Accessed 22 Jan 2014.

  31. Murphy BE. Cortisol production and inactivation by the human lung during gestation and infancy. J Clin Endocrinol Metab. 1978;47(2):243–8. doi:10.1210/jcem-47-2-243.

    CAS  PubMed  Google Scholar 

  32. Abramovitz M, Branchaud CL, Murphy BE. Cortisol-cortisone interconversion in human fetal lung: contrasting results using explant and monolayer cultures suggest that 11 beta-hydroxysteroid dehydrogenase (EC 1.1.1.146) comprises two enzymes. J Clin Endocrinol Metab. 1982;54(3):563–8. doi:10.1210/jcem-54-3-563.

    CAS  PubMed  Google Scholar 

  33. Dimitriou T, Maser-Gluth C, Remer T. Adrenocortical activity in healthy children is associated with fat mass. Am J Clin Nutr. 2003;77(3):731–6. http://www.ncbi.nlm.nih.gov/pubmed/12600869.

    CAS  PubMed  Google Scholar 

  34. Toogood AA, Taylor NF, Shalet SM, Monson JP. Sexual dimorphism of cortisol metabolism is maintained in elderly subjects and is not oestrogen dependent. Clin Endocrinol (Oxf). 2000;52(1):61–6. http://www.ncbi.nlm.nih.gov/pubmed/10651754. Accessed 22 Jan 2014.

  35. Vierhapper H, Heinze G, Nowotny P. Sex-specific difference in the interconversion of cortisol and cortisone in men and women. Obesity (Silver Spring). 2007;15(4):820–4. doi:10.1038/oby.2007.592.

    CAS  Google Scholar 

  36. Finken MJ, Andrews RC, Andrew R, Walker BR. Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11beta-hydroxysteroid dehydrogenases. J Clin Endocrinol Metab. 1999;84(9):3316–21. doi:10.1210/jcem.84.9.6009.

    CAS  PubMed  Google Scholar 

  37. Gathercole LL, Lavery GG, Morgan SA, et al. 11β-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev. 2013;34(4):525–55. doi:10.1210/er.2012-1050.

    CAS  PubMed  Google Scholar 

  38. Nixon M, Wake DJ, Livingstone DE, et al. Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. Diabetes. 2012;61(4):790–6. doi:10.2337/db11-0931.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Paulsen SK, Pedersen SB, Fisker S, Richelsen B. 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization. Obesity (Silver Spring). 2007;15(8):1954–60. doi:10.1038/oby.2007.233.

    CAS  Google Scholar 

  40. Gomez-Sanchez EP, Ganjam V, Chen YJ, et al. Regulation of 11 beta-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol. Am J Physiol Endocrinol Metab. 2003;285(2):E272–9. doi:10.1152/ajpendo.00409.2002.

    CAS  PubMed  Google Scholar 

  41. Quirk SJ, Slattery JA, Funder JW. Epithelial and adipose cells isolated from mammary glands of pregnant and lactating rats differ in 11 beta-hydroxysteroid dehydrogenase activity. J Steroid Biochem Mol Biol. 1990;37(4):529–34. http://www.ncbi.nlm.nih.gov/pubmed/2278836. Accessed 31 Dec 2013.

  42. Goedecke JH, Wake DJ, Levitt NS, et al. Glucocorticoid metabolism within superficial subcutaneous rather than visceral adipose tissue is associated with features of the metabolic syndrome in South African women. Clin Endocrinol (Oxf). 2006;65(1):81–7. doi:10.1111/j.1365-2265.2006.02552.x.

    CAS  Google Scholar 

  43. Veilleux A, Laberge PY, Morency J, Noël S, Luu-The V, Tchernof A. Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue. J Steroid Biochem Mol Biol. 2010;122(1–3):28–34. doi:10.1016/j.jsbmb.2010.02.024.

    CAS  PubMed  Google Scholar 

  44. Tomlinson JW, Moore J, Cooper MS, et al. Regulation of expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology. 2001;142(5):1982–9.

    CAS  PubMed  Google Scholar 

  45. Friedberg M, Zoumakis E, Hiroi N, Bader T, Chrousos GP, Hochberg Z. Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. J Clin Endocrinol Metab. 2003;88(1):385–93. doi:10.1210/jc.2002-020510.

    CAS  PubMed  Google Scholar 

  46. Handoko K, Yang K, Strutt B, Khalil W, Killinger D. Insulin attenuates the stimulatory effects of tumor necrosis factor alpha on 11beta-hydroxysteroid dehydrogenase 1 in human adipose stromal cells. J Steroid Biochem Mol Biol. 2000;72(3–4):163–8. http://www.ncbi.nlm.nih.gov/pubmed/10775808. Accessed 31 Dec 2013.

  47. Esteves CL, Kelly V, Breton A, et al. Proinflammatory cytokine induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in human adipocytes is mediated by MEK, C/EBPβ, and NF-κB/RelA. J Clin Endocrinol Metab. 2014;99(1):E160–8. doi:10.1210/jc.2013-1708.

    PubMed  Google Scholar 

  48. Bujalska IJ, Walker EA, Hewison M, Stewart PM. A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells. J Clin Endocrinol Metab. 2002;87(3):1205–10. doi:10.1210/jcem.87.3.8301.

    CAS  PubMed  Google Scholar 

  49. Bujalska IJ, Gathercole LL, Tomlinson JW, et al. A novel selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis. J Endocrinol. 2008;197(2):297–307. doi:10.1677/JOE-08-0050.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Livingstone DE, Kenyon CJ, Walker BR. Mechanisms of dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 in obese Zucker rats. J Endocrinol. 2000;167(3):533–9. http://www.ncbi.nlm.nih.gov/pubmed/11115781. Accessed 7 Mar 2014.

  51. Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology. 2000;141(2):560–3. doi:10.1210/endo.141.2.7297.

    CAS  PubMed  Google Scholar 

  52. Morton NM, Ramage L, Seckl JR. Down-regulation of adipose 11beta-hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism counteracting metabolic disease. Endocrinology. 2004;145(6):2707–12. doi:10.1210/en.2003-1674.

    CAS  PubMed  Google Scholar 

  53. Drake AJ, Livingstone DEW, Andrew R, Seckl JR, Morton NM, Walker BR. Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feeding in Wistar rats. Endocrinology. 2005;146(2):913–9. doi:10.1210/en.2004-1063.

    CAS  PubMed  Google Scholar 

  54. Morton NM, Holmes MC, Fiévet C, et al. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem. 2001;276(44):41293–300. doi:10.1074/jbc.M103676200.

    CAS  PubMed  Google Scholar 

  55. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294(5549):2166–70. doi:10.1126/science.1066285.

    CAS  PubMed  Google Scholar 

  56. Rask E. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86(3):1418–21. doi:10.1210/jc.86.3.1418.

    CAS  PubMed  Google Scholar 

  57. Lindsay RS. Subcutaneous adipose 11-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. 2003;88(6):2738–44. doi:10.1210/jc.2002-030017.

    CAS  PubMed  Google Scholar 

  58. Veilleux A, Rhéaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009;94(9):3550–7. doi:10.1210/jc.2008-2011.

    CAS  PubMed  Google Scholar 

  59. Lee JH, Gao Z, Ye J. Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α. Am J Physiol Endocrinol Metab. 2013;304(10):E1035–41. doi:10.1152/ajpendo.00029.2013.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. McCormick KL, Wang X, Mick GJ. Evidence that the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is regulated by pentose pathway flux. Studies in rat adipocytes and microsomes. J Biol Chem. 2006;281(1):341–7. doi:10.1074/jbc.M506026200.

    CAS  PubMed  Google Scholar 

  61. Gout J, Tirard J, Thévenon C, Riou J-P, Bégeot M, Naville D. CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11beta-hydroxysteroid dehydrogenase encoding gene in adipose cells. Biochimie. 2006;88(9):1115–24. doi:10.1016/j.biochi.2006.05.020.

    CAS  PubMed  Google Scholar 

  62. Esteves CL, Kelly V, Bégay V, et al. Regulation of adipocyte 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by CCAAT/enhancer-binding protein (C/EBP) β isoforms LIP and LAP. PLoS One. 2012;7(5):e37953. doi:10.1371/journal.pone.0037953.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Amatruda JM, Danahy SA, Chang CL. The effects of glucocorticoids on insulin-stimulated lipogenesis in primary cultures of rat hepatocytes. Biochem J. 1983;212(1):135–41. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1152020&tool=pmcentrez&rendertype=abstract.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Dolinsky VW, Douglas DN, Lehner R, Vance DE. Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone. Biochem J. 2004;378(Pt 3):967–74. doi:10.1042/BJ20031320.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Baxter JD, Forsham PH. Tissue effects of glucocorticoids. Am J Med. 1972;53(5):573–89. http://www.ncbi.nlm.nih.gov/pubmed/4342884. Accessed 22 Jan 2014.

  66. Paterson JM, Morton NM, Fievet C, et al. Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci U S A. 2004;101(18):7088–93. doi:10.1073/pnas.0305524101.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM. Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues. J Clin Endocrinol Metab. 1998;83(4):1325–35. doi:10.1210/jcem.83.4.4706.

    CAS  PubMed  Google Scholar 

  68. Jamieson PM, Walker BR, Chapman KE, Andrew R, Rossiter S, Seckl JR. 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver. J Endocrinol. 2000;165(3):685–92. http://www.ncbi.nlm.nih.gov/pubmed/10828853. Accessed 7 Mar 2014.

  69. Candia R, Riquelme A, Baudrand R, et al. Overexpression of 11β-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non-alcoholic fatty liver disease. Liver Int. 2012;32(3):392–9. doi:10.1111/j.1478-3231.2011.02685.x.

    CAS  PubMed  Google Scholar 

  70. Baudrand R, Carvajal CA, Riquelme A, et al. Overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in hepatic and visceral adipose tissue is associated with metabolic disorders in morbidly obese patients. Obes Surg. 2010;20(1):77–83. doi:10.1007/s11695-009-9937-0.

    PubMed  Google Scholar 

  71. Konopelska S, Kienitz T, Hughes B, et al. Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis. Clin Endocrinol (Oxf). 2009;70(4):554–60. doi:10.1111/j.1365-2265.2008.03358.x.

    CAS  Google Scholar 

  72. Torrecilla E, Fernández-Vázquez G, Vicent D, et al. Liver upregulation of genes involved in cortisol production and action is associated with metabolic syndrome in morbidly obese patients. Obes Surg. 2012;22(3):478–86. doi:10.1007/s11695-011-0524-9.

    PubMed  Google Scholar 

  73. Valsamakis G, Anwar A, Tomlinson JW, et al. 11Beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89(9):4755–61. doi:10.1210/jc.2003-032240.

    CAS  PubMed  Google Scholar 

  74. Ahmed A, Rabbitt E, Brady T, et al. A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease. PLoS One. 2012;7(2):e29531. doi:10.1371/journal.pone.0029531.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Whorwood CB, Donovan SJ, Flanagan D, Phillips DIW, Byrne CD. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes. 2002;51(4):1066–75. http://www.ncbi.nlm.nih.gov/pubmed/11916927.

    CAS  PubMed  Google Scholar 

  76. Whorwood CB, Donovan SJ, Wood PJ, Phillips DI. Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11β-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? J Clin Endocrinol Metab. 2001;86(5):2296–308.

    CAS  PubMed  Google Scholar 

  77. Morgan SA, Sherlock M, Gathercole LL, et al. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes. 2009;58(11):2506–15. doi:10.2337/db09-0525.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Abdallah BM, Beck-Nielsen H, Gaster M. Increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in type 2 diabetic myotubes. Eur J Clin Invest. 2005;35(10):627–34. doi:10.1111/j.1365-2362.2005.01552.x.

    CAS  PubMed  Google Scholar 

  79. Zhang M, Lv X-Y, Li J, Xu Z-G, Chen L. Alteration of 11beta-hydroxysteroid dehydrogenase type 1 in skeletal muscle in a rat model of type 2 diabetes. Mol Cell Biochem. 2009;324(1–2):147–55. doi:10.1007/s11010-008-9993-0.

    CAS  PubMed  Google Scholar 

  80. Kilgour AHM, Gallagher IJ, Maclullich AMJ, et al. Increased skeletal muscle 11βHSD1 mRNA is associated with lower muscle strength in ageing. PLoS One. 2013;8(12):e84057. doi:10.1371/journal.pone.0084057.

    PubMed Central  PubMed  Google Scholar 

  81. Vukelic S, Stojadinovic O, Pastar I, et al. Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem. 2011;286(12):10265–75. doi:10.1074/jbc.M110.188268.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Tiganescu A, Walker EA, Hardy RS, Mayes AE, Stewart PM. Localization, age- and site-dependent expression, and regulation of 11β-hydroxysteroid dehydrogenase type 1 in skin. J Invest Dermatol. 2011;131(1):30–6. doi:10.1038/jid.2010.257.

    CAS  PubMed  Google Scholar 

  83. Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol. 2010;144(5):666–72. doi:10.1001/archderm.144.5.666.Looking.

    Google Scholar 

  84. Slominski A, Zbytek B, Nikolakis G, et al. Steroidogenesis in the skin: implications for local immune functions. J Steroid Biochem Mol Biol. 2013;137:107–23. doi:10.1016/j.jsbmb.2013.02.006.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Terao M, Murota H, Kimura A, et al. 11β-Hydroxysteroid dehydrogenase-1 is a novel regulator of skin homeostasis and a candidate target for promoting tissue repair. PLoS One. 2011;6(9):e25039. doi:10.1371/journal.pone.0025039.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Cirillo N, Prime SS. Keratinocytes synthesize and activate cortisol. J Cell Biochem. 2011;112(6):1499–505. doi:10.1002/jcb.23081.

    CAS  PubMed  Google Scholar 

  87. Napolitano A, Voice MW, Edwards CR, Seckl JR, Chapman KE. 11Beta-hydroxysteroid dehydrogenase 1 in adipocytes: expression is differentiation-dependent and hormonally regulated. J Steroid Biochem Mol Biol. 1998;64(5–6):251–60. http://www.ncbi.nlm.nih.gov/pubmed/9618026. Accessed 3 Feb 2014.

  88. Tiganescu A, Hupe M, Uchida Y, Mauro T, Elias PM, Holleran W. Increased glucocorticoid activation during mouse skin wound healing. J Endocrinol. 2014;221(1):51–61. doi:10.1530/JOE-13-0420.

    CAS  PubMed  Google Scholar 

  89. Tiganescu A, Tahrani AA, Morgan SA, et al. 11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects. J Clin Invest. 2013;123(7):3051–60. doi:10.1172/JCI64162.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Brem AS, Bina RB, King TC, Morris DJ. Localization of 2 11beta-OH steroid dehydrogenase isoforms in aortic endothelial cells. Hypertension. 1998;31(1 Pt 2):459–62. http://www.ncbi.nlm.nih.gov/pubmed/9453345. Accessed 14 Feb 2014.

  91. Walker BR, Yau JL, Brett LP, et al. 11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids. Endocrinology. 1991;129(6):3305–12. doi:10.1210/endo-129-6-3305.

    CAS  PubMed  Google Scholar 

  92. Atalar F, Gormez S, Caynak B, et al. The role of mediastinal adipose tissue 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid expression in the development of coronary atherosclerosis in obese patients with ischemic heart disease. Cardiovasc Diabetol. 2012;11:115. doi:10.1186/1475-2840-11-115.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Atalar F, Vural B, Ciftci C, et al. 11β-hydroxysteroid dehydrogenase type 1 gene expression is increased in ascending aorta tissue of metabolic syndrome patients with coronary artery disease. Genet Mol Res. 2012;11(3):3122–32. doi:10.4238/2012.August.31.10.

    CAS  PubMed  Google Scholar 

  94. Hermanowski-Vosatka A, Balkovec JM, Cheng K, et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005;202(4):517–27. doi:10.1084/jem.20050119.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Nuotio-Antar AM, Hachey DL, Hasty AH. Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. Am J Physiol Endocrinol Metab. 2007;293(6):E1517–28. doi:10.1152/ajpendo.00522.2007.

    CAS  PubMed  Google Scholar 

  96. Small GR, Hadoke PWF, Sharif I, et al. Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. Proc Natl Acad Sci U S A. 2005;102(34):12165–70. doi:10.1073/pnas.0500641102.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Brown ES. Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy. Ann N Y Acad Sci. 2009;1179:41–55. doi:10.1111/j.1749-6632.2009.04981.x.

    CAS  PubMed  Google Scholar 

  98. Swaab DF, Bao A-M, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4(2):141–94. doi:10.1016/j.arr.2005.03.003.

    CAS  PubMed  Google Scholar 

  99. Korbonits M, Bujalska I, Shimojo M, et al. Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors. J Clin Endocrinol Metab. 2001;86(6):2728–33. doi:10.1210/jcem.86.6.7563.

    CAS  PubMed  Google Scholar 

  100. Moisan MP, Seckl JR, Edwards CR. 11 beta-hydroxysteroid dehydrogenase bioactivity and messenger RNA expression in rat forebrain: localization in hypothalamus, hippocampus, and cortex. Endocrinology. 1990;127(3):1450–5. doi:10.1210/endo-127-3-1450.

    CAS  PubMed  Google Scholar 

  101. Gomez-Sanchez EP, Romero DG, de Rodriguez AF, Warden MP, Krozowski Z, Gomez-Sanchez CE. Hexose-6-phosphate dehydrogenase and 11beta-hydroxysteroid dehydrogenase-1 tissue distribution in the rat. Endocrinology. 2008;149(2):525–33. doi:10.1210/en.2007-0328.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Lakshmi V, Sakai RR, McEwen BS, Monder C. Regional distribution of 11 beta-hydroxysteroid dehydrogenase in rat brain. Endocrinology. 1991;128(4):1741–8. doi:10.1210/endo-128-4-1741.

    CAS  PubMed  Google Scholar 

  103. Rajan V, Edwards RW, Seckl JR. 11 beta-hydroxysteroid dehydrogenase in cultured cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity hippocampal. J Neurosci. 1996;76(1):65–70.

    Google Scholar 

  104. Wyrwoll CS, Holmes MC, Seckl JR. 11β-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol. 2011;32(3):265–86. doi:10.1016/j.yfrne.2010.12.001.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Tomlinson JW, Durrani OM, Bujalska IJ, et al. The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2010;95(1):398–406. doi:10.1210/jc.2009-0873.

    CAS  PubMed  Google Scholar 

  106. Sandeep TC, Yau JLW, MacLullich AMJ, et al. 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci U S A. 2004;101(17):6734–9. doi:10.1073/pnas.0306996101.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–23. doi:10.1056/NEJMra050541.

    CAS  PubMed  Google Scholar 

  108. Chapman KE, Coutinho AE, Gray M, Gilmour JS, Savill JS, Seckl JR. The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol Cell Endocrinol. 2009;301(1-2):123–31. doi:10.1016/j.mce.2008.09.031.

    CAS  PubMed  Google Scholar 

  109. Coutinho AE, Brown JK, Yang F, et al. Mast cells express 11β-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation. PLoS One. 2013;8(1):e54640. doi:10.1371/journal.pone.0054640.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Thieringer R, Le Grand CB, Carbin L, et al. 11 Beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol. 2001;167(1):30–5. http://www.ncbi.nlm.nih.gov/pubmed/11418628.

    CAS  PubMed  Google Scholar 

  111. Zhang TY, Ding X, Daynes RA, Alerts E. Regulation of glucocorticoid activities 1. J Immunol. 2005;174(2):879–89.

    CAS  PubMed  Google Scholar 

  112. Freeman L, Hewison M, Hughes SV, et al. Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood. 2005;106(6):2042–9. doi:10.1182/blood-2005-01-0186.

    CAS  PubMed  Google Scholar 

  113. Gilmour JS, Coutinho AE, Cailhier J, et al. Local amplification of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J Immunol. 2006;176(12):7605–11.

    CAS  PubMed  Google Scholar 

  114. Zhang TY, Daynes RA. Macrophages from 11beta-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-beta-mediated up-regulation of SHIP1 expression. J Immunol. 2007;179(9):6325–35.

    Google Scholar 

  115. Coutinho AE, Gray M, Brownstein DG, et al. 11β-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice. Endocrinology. 2012;153(1):234–40. doi:10.1210/en.2011-1398.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Zbánková S, Bryndová J, Leden P, Kment M, Svec A, Pácha J. 11beta-hydroxysteroid dehydrogenase 1 and 2 expression in colon from patients with ulcerative colitis. J Gastroenterol Hepatol. 2007;22(7):1019–23. doi:10.1111/j.1440-1746.2006.04529.x.

    PubMed  Google Scholar 

  117. Stegk JP, Ebert B, Martin H-J, Maser E. Expression profiles of human 11beta-hydroxysteroid dehydrogenases type 1 and type 2 in inflammatory bowel diseases. Mol Cell Endocrinol. 2009;301(1–2):104–8. doi:10.1016/j.mce.2008.10.030.

    CAS  PubMed  Google Scholar 

  118. Cooper MS, Kriel H, Sayers A, et al. Can 11β-hydroxysteroid dehydrogenase activity predict the sensitivity of bone to therapeutic glucocorticoids in inflammatory bowel disease? Calcif Tissue Int. 2011;89(3):246–51. doi:10.1007/s00223-011-9512-2.

    CAS  PubMed  Google Scholar 

  119. Ergang P, Vytáčková K, Svec J, Bryndová J, Mikšík I, Pácha J. Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat. J Steroid Biochem Mol Biol. 2011;126(1–2):19–25. doi:10.1016/j.jsbmb.2011.04.002.

    CAS  PubMed  Google Scholar 

  120. Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM. Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone. Bone. 2000;27(3):375–81. http://www.ncbi.nlm.nih.gov/pubmed/10962348. Accessed 14 Feb 2014.

  121. Bellows CG, Ciaccia A, Heersche JN. Osteoprogenitor cells in cell populations derived from mouse and rat calvaria differ in their response to corticosterone, cortisol, and cortisone. Bone. 1998;23(2):119–25. http://www.ncbi.nlm.nih.gov/pubmed/9701470. Accessed 14 Feb 2014.

  122. Hardy R, Rabbitt EH, Filer A, et al. Local and systemic glucocorticoid metabolism in inflammatory arthritis. Ann Rheum Dis. 2008;67(9):1204–10. doi:10.1136/ard.2008.090662.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Schmidt M, Weidler C, Naumann H, Anders S, Schölmerich J, Straub RH. Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system? Arthritis Rheum. 2005;52(6):1711–20. doi:10.1002/art.21091.

    CAS  PubMed  Google Scholar 

  124. Ergang P, Leden P, Vagnerová K, et al. Local metabolism of glucocorticoids and its role in rat adjuvant arthritis. Mol Cell Endocrinol. 2010;323(2):155–60. doi:10.1016/j.mce.2010.03.003.

    CAS  PubMed  Google Scholar 

  125. Lavery GG, Walker EA, Tiganescu A, et al. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. J Clin Endocrinol Metab. 2008;93(10):3827–32. doi:10.1210/jc.2008-0743.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Morgan SA, Tomlinson JW. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2010;19(9):1067–76. doi:10.1517/13543784.2010.504713.

    CAS  PubMed  Google Scholar 

  127. Monder C, Lakshmi V. Evidence for kinetically distinct forms of corticosteroid 11 beta-dehydrogenase in rat liver microsomes. J Steroid Biochem. 1989;32(1A):77–83. http://www.ncbi.nlm.nih.gov/pubmed/2913404. Accessed 23 Jan 2014.

  128. Schweizer RAS, Atanasov AG, Frey BM, Odermatt A. A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11beta-HSD1 reductase activity. Mol Cell Endocrinol. 2003;212(1–2):41–9. http://www.ncbi.nlm.nih.gov/pubmed/14654249. Accessed 23 Jan 2014.

  129. Diederich S, Grossmann C, Hanke B, et al. In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Eur J Endocrinol. 2000;142(2):200–7. http://www.ncbi.nlm.nih.gov/pubmed/10664531.

    CAS  PubMed  Google Scholar 

  130. Latif SA, Pardo HA, Hardy MP, Morris DJ. Endogenous selective inhibitors of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin. Mol Cell Endocrinol. 2005;243(1–2):43–50. doi:10.1016/j.mce.2005.08.006.

    CAS  PubMed  Google Scholar 

  131. Atanasov AG, Dzyakanchuk AA, Schweizer RAS, Nashev LG, Maurer EM, Odermatt A. Coffee inhibits the reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee? FEBS Lett. 2006;580(17):4081–5. doi:10.1016/j.febslet.2006.06.046.

    CAS  PubMed  Google Scholar 

  132. Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 2003;88(1):285–91. doi:10.1210/jc.2002-021194.

    CAS  PubMed  Google Scholar 

  133. Reuters T. The changing role of chemistry in drug discovery. 2011. http://thomsonreuters.com/content/dam/openweb/documents/pdf/pharma-life-sciences/report/international-year-of-chemistry-report-drug-discovery.pdf.

  134. Boyle CD, Kowalski TJ. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents. Expert Opin Ther Pat. 2009;19(6):801–25. doi: 10.1517/13543770902967658.

  135. Rosenstock J, Banarer S, Fonseca VA, et al. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care. 2010;33(7):1516–22. doi:10.2337/dc09-2315.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Shah S, Hermanowski-Vosatka A, Gibson K, et al. Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension. J Am Soc Hypertens. 2011;5(3):166–76. doi:10.1016/j.jash.2011.01.009.

    CAS  PubMed  Google Scholar 

  137. Brown RW, Chapman KE, Edwards CR, Seckl JR. Human placental 11 beta-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent isoform. Endocrinology. 1993;132(6):2614–21. doi:10.1210/endo.132.6.8504762.

    CAS  PubMed  Google Scholar 

  138. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994;105(2):R11–7. http://www.ncbi.nlm.nih.gov/pubmed/7859916. Accessed 5 Feb 2014.

  139. Persson B, Kallberg Y, Bray JE, et al. The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chem Biol Interact. 2009;178(1–3):94–8. doi:10.1016/j.cbi.2008.10.040.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Agarwal AK, Rogerson FM, Mune T, White PC. Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11 beta-hydroxysteroid dehydrogenase. Genomics. 1995;29(1):195–9. doi:10.1006/geno.1995.1231.

    CAS  PubMed  Google Scholar 

  141. Brown RW, Chapman KE, Kotelevtsev Y, et al. Cloning and production of antisera to human placental 11β-hydroxysteroid dehydrogenase type 2. Biochem J. 1996;313:1007–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Stewart PM, Murry BA, Mason JI. Human kidney 11 beta-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. J Clin Endocrinol Metab. 1994;79(2):480–4. doi:10.1210/jcem.79.2.8045966.

    CAS  PubMed  Google Scholar 

  143. Dave-Sharma S, Wilson RC, Harbison MD, et al. Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 1998;83(7):2244–54. doi:10.1210/jcem.83.7.4986.

    CAS  PubMed  Google Scholar 

  144. Wilson RC, Krozowski ZS, Li K, et al. A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 1995;80(7):2263–6. doi:10.1210/jcem.80.7.7608290.

    CAS  PubMed  Google Scholar 

  145. Mune T, Rogerson FM, Nikkilä H, Agarwal AK, White PC. Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet. 1995;10(4):394–9. doi:10.1038/ng0895-394.

    CAS  PubMed  Google Scholar 

  146. Osinski PA. Steroid 11beta-ol dehydrogenase in human placenta. Nature. 1960;187:777. http://www.ncbi.nlm.nih.gov/pubmed/14429221. Accessed 31 Dec 2013.

  147. Waffarn F, Davis EP. Effects of antenatal corticosteroids on the hypothalamic-pituitary-adrenocortical axis of the fetus and newborn: experimental findings and clinical considerations. Am J Obstet Gynecol. 2012;207(6):446–54. doi:10.1016/j.ajog.2012.06.012.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Wyrwoll CS, Holmes MC. Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways. Neuroendocrinology. 2012;95(1):47–55. doi:10.1159/000331345.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol. 1999;94(2):213–8. http://www.ncbi.nlm.nih.gov/pubmed/10432130. Accessed 14 Feb 2014.

  150. Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal “programming” of adult pathophysiology. Nat Clin Pract Endocrinol Metab. 2007;3(6):479–88. doi:10.1038/ncpendmet0515.

    CAS  PubMed  Google Scholar 

  151. Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM. Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest. 2004;114(8):1146–57. doi:10.1172/JCI21647.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Marsit CJ, Maccani MA, Padbury JF, Lester BM. Placental 11-beta hydroxysteroid dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome. PLoS One. 2012;7(3):e33794. doi:10.1371/journal.pone.0033794.

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Baserga M, Kaur R, Hale MA, et al. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol. 2010;299(1):334–42. doi:10.1152/ajpregu.00122.2010.

    Google Scholar 

  154. Kostadinova RM, Nawrocki AR, Frey FJ, Frey BM. Tumor necrosis factor alpha and phorbol 12-myristate-13-acetate down-regulate human 11beta-hydroxysteroid dehydrogenase type 2 through p50/p50 NF-kappaB homodimers and Egr-1. FASEB J. 2005;19(6):650–2. doi:10.1096/fj.04-2820fje.

    CAS  PubMed  Google Scholar 

  155. Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CR, Seckl JR. Regulation of 11 beta-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol. 1993;139(1):27–35. http://www.ncbi.nlm.nih.gov/pubmed/8254291. Accessed 13 Feb 2014.

  156. Rubis B, Krozowski Z, Trzeciak WH. Arginine vasopressin stimulates 11beta-hydroxysteroid dehydrogenase type 2 expression in the mineralocorticosteroid target cells. Mol Cell Endocrinol. 2006;256(1–2):17–22. doi:10.1016/j.mce.2006.04.032.

    CAS  PubMed  Google Scholar 

  157. Clarke KA, Ward JW, Forhead AJ, Giussani DA, Fowden AL. Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol. J Endocrinol. 2002;172(3):527–34. http://www.ncbi.nlm.nih.gov/pubmed/11874701. Accessed 13 Feb 2014.

  158. Suzuki S, Koyama K, Darnel A, et al. Dexamethasone upregulates 11beta-hydroxysteroid dehydrogenase type 2 in BEAS-2B cells. Am J Respir Crit Care Med. 2003;167(9):1244–9. doi:10.1164/rccm.200210-1139OC.

    PubMed  Google Scholar 

  159. Heiniger CD, Kostadinova RM, Rochat MK, et al. Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1. FASEB J. 2003;17(8):917–9. doi:10.1096/fj.02-0582fje.

    CAS  PubMed  Google Scholar 

  160. Fukushima K, Funayama Y, Yonezawa H, et al. Aldosterone enhances 11beta-hydroxysteroid dehydrogenase type 2 expression in colonic epithelial cells in vivo. Scand J Gastroenterol. 2005;40(7):850–7. doi:10.1080/00365520510015700.

    PubMed  Google Scholar 

  161. Geerling JC, Loewy AD. Aldosterone in the brain. Am J Physiol Renal Physiol. 2009;297(3):F559–76. doi:10.1152/ajprenal.90399.2008.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Holmes MC, Sangra M, French KL, et al. 11beta-hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids. Neuroscience. 2006;137(3):865–73. doi:10.1016/j.neuroscience.2005.09.037.

    CAS  PubMed  Google Scholar 

  163. Noguchi KK, Lau K, Smith DJ, Swiney BS, Farber NB. Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis. Neurobiol Dis. 2011;43(2):356–63. doi:10.1016/j.nbd.2011.04.004.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Roland BL, Li KX, Funder JW. Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology. 1995;136(10):4697–700. doi:10.1210/endo.136.10.7664691.

    CAS  PubMed  Google Scholar 

  165. Christy C, Hadoke PWF, Paterson JM, Mullins JJ, Seckl JR, Walker BR. 11beta-hydroxysteroid dehydrogenase type 2 in mouse aorta: localization and influence on response to glucocorticoids. Hypertension. 2003;42(4):580–7. doi:10.1161/01.HYP.0000088855.06598.5B.

    CAS  PubMed  Google Scholar 

  166. Deuchar GA, McLean D, Hadoke PWF, et al. 11β-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe-/- mice. Endocrinology. 2011;152(1):236–46. doi:10.1210/en.2010-0925.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Leckie C, Chapman KE, Edwards CR, Seckl JR. LLC-PK1 cells model 11 beta-hydroxysteroid dehydrogenase type 2 regulation of glucocorticoid access to renal mineralocorticoid receptors. Endocrinology. 1995;136(12):5561–9. doi:10.1210/endo.136.12.7588309.

    CAS  PubMed  Google Scholar 

  168. Henschkowski J, Stuck AE, Frey BM, et al. Age-dependent decrease in 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in hypertensive patients. Am J Hypertens. 2008;21(6):644–9. doi:10.1038/ajh.2008.152.

    CAS  PubMed  Google Scholar 

  169. Ferrari P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim Biophys Acta. 2010;1802(12):1178–87. doi:10.1016/j.bbadis.2009.10.017.

    CAS  PubMed  Google Scholar 

  170. Mongia A, Vecker R, George M, et al. Role of 11βHSD type 2 enzyme activity in essential hypertension and children with chronic kidney disease (CKD). J Clin Endocrinol Metab. 2012;97(10):3622–9. doi:10.1210/jc.2012-1411.

    CAS  PubMed  Google Scholar 

  171. Watson B, Bergman SM, Myracle A, Callen DF, Acton RT, Warnock DG. Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. Hypertension. 1996;28(3):478–82. http://www.ncbi.nlm.nih.gov/pubmed/8794836. Accessed 2 Mar 2014.

  172. Whorwood CB, Ricketts ML, Stewart PM. Epithelial cell localization of type 2 11 beta-hydroxysteroid dehydrogenase in rat and human colon. Endocrinology. 1994;135(6):2533–41. doi:10.1210/endo.135.6.7988441.

    CAS  PubMed  Google Scholar 

  173. Zhang M-Z, Xu J, Yao B, et al. Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest. 2009;119(4):876–85. doi:10.1172/JCI37398.

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Smith RE, Maguire JA, Stein-Oakley AN, et al. Localization of 11 beta-hydroxysteroid dehydrogenase type II in human epithelial tissues. J Clin Endocrinol Metab. 1996;81(9):3244–8. doi:10.1210/jcem.81.9.8784076.

    CAS  PubMed  Google Scholar 

  175. Shimojo M, Ricketts ML, Petrelli MD, et al. Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization. Endocrinology. 1997;138(3):1305–11. doi:10.1210/endo.138.3.4994.

    CAS  PubMed  Google Scholar 

  176. Perogamvros I, Keevil BG, Ray DW, Trainer PJ. Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metab. 2010;95(11):4951–8. doi:10.1210/jc.2010-1215.

    CAS  PubMed  Google Scholar 

  177. Bocchi B, Kenouch S, Lamarre-Cliche M, et al. Impaired 11-beta hydroxysteroid dehydrogenase type 2 activity in sweat gland ducts in human essential hypertension. Hypertension. 2004;43(4):803–8. doi:10.1161/01.HYP.0000121362.64182.ad.

    CAS  PubMed  Google Scholar 

  178. Ulick S, Levine LS, Gunczler P, et al. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab. 1979;49(5):757–64. doi:10.1210/jcem-49-5-757.

    CAS  PubMed  Google Scholar 

  179. Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J Clin Invest. 1988;82(1):340–9. doi:10.1172/JCI113592.

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Stewart PM, Krozowski ZS, Gupta A, et al. Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene. Lancet. 1996;347(8994):88–91. http://www.ncbi.nlm.nih.gov/pubmed/8538347. Accessed 12 Feb 2014.

  181. Stewart PM, Wallace AM, Valentino R, Burt D, Shackleton CH, Edwards CR. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet. 1987;2(8563):821–4. http://www.ncbi.nlm.nih.gov/pubmed/2889032. Accessed 12 Feb 2014.

  182. Tomlinson JW, Draper N, Mackie J, et al. Absence of Cushingoid phenotype in a patient with Cushing’s disease due to defective cortisone to cortisol conversion. J Clin Endocrinol Metab. 2002;87(1):57–62. doi:10.1210/jcem.87.1.8189.

    CAS  PubMed  Google Scholar 

  183. Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, Bujalska IJ, Stewart PM, Tomlinson JW, Lavery GG. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci USA. 2014;111(24):E2482-91. doi: 10..1073/pnas.1323681111

    Google Scholar 

  184. Cooper MS, Syddall HE, Fall CHD, et al. Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire Cohort Study. Clin Endocrinol (Oxf). 2005;62(6):692–7. doi:10.1111/j.1365-2265.2005.02281.x.

    CAS  Google Scholar 

  185. Overman RA, Yeh J-Y, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken). 2013;65(2):294–8. doi:10.1002/acr.21796.

    Google Scholar 

  186. Fardet L, Flahault A, Kettaneh A, et al. Corticosteroid-induced clinical adverse events: frequency, risk factors and patient’s opinion. Br J Dermatol. 2007;157(1):142–8. doi:10.1111/j.1365-2133.2007.07950.x.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Diabetes and Endocrinology, St Vincent’s University Hospital, Dublin, Leisnter, Ireland

    Conor Woods M.B.B.Ch., M.R.C.P.

  2. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Radcliffe Department of Medicine, Churchill Hospital, Oxford, UK

    Jeremy W. Tomlinson

Authors
  1. Conor Woods M.B.B.Ch., M.R.C.P.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy W. Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy W. Tomlinson .

Editor information

Editors and Affiliations

  1. Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, California, USA

    Jen-Chywan Wang

  2. Division of Endocrinology Metabolism & Lipid Research, Department of Internal Medicine, Washington University School of Medicine Division of Endocrinology, St. Louis, Missouri, USA

    Charles Harris

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Woods, C., Tomlinson, J.W. (2015). The Dehydrogenase Hypothesis. In: Wang, JC., Harris, C. (eds) Glucocorticoid Signaling. Advances in Experimental Medicine and Biology, vol 872. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2895-8_16

Download citation

Publish with us

Policies and ethics

Search

Navigation