11β-Hydroxysteroid dehydrogenase type 1 explained

11β-Hydroxysteroid dehydrogenase type 1, also known as cortisone reductase, is an NADPH-dependent enzyme highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system. In these tissues, HSD11B1 reduces cortisone to the active hormone cortisol that activates glucocorticoid receptors. It belongs to the family of short-chain dehydrogenases. It is encoded by the gene.

Function

The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Two transcript variants encoding the same protein have been found for this gene.^[1]

Clinical significance

11β-HSD1 is inhibited by carbenoxolone, a drug typically used in the treatment of peptic ulcers. Moreover, 18alpha-glycyrrhizic acid from the root of glycyrrhiza glabra was discovered as an inhibitor.^[2]

Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and hence may explain why aspirin improves glycemic control in type 2 diabetes.^[3] Epigallocatechin gallate from green tea can also potently inhibit this enzyme;^[4] green tea is a complex mixture of various phenolics with contents varying with production and processing, and some of the phenolics are known HDAC inhibitors that alter genetic expression. EGCG as usually consumed in green tea is poorly absorbed into the bloodstream. More research is needed to reach firm conclusions.

See also

• Cortisone reductase deficiency
• 11β-hydroxysteroid dehydrogenase type 2

References

Further reading

• White PC, Mune T, Agarwal AK . 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess . Endocrine Reviews . 18 . 1 . 135–56 . February 1997 . 10.1210/edrv.18.1.0288 . 9034789 . free .
• Agarwal AK . Cortisol metabolism and visceral obesity: role of 11beta-hydroxysteroid dehydrogenase type I enzyme and reduced co-factor NADPH . Endocrine Research . 29 . 4 . 411–8 . November 2003 . 14682470 . 10.1081/ERC-120026947 . 32163545 .
• Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM . 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response . Endocrine Reviews . 25 . 5 . 831–66 . October 2004 . 15466942 . 10.1210/er.2003-0031 . free .
• Wake DJ, Walker BR . Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity . Endocrine . 29 . 1 . 101–8 . February 2006 . 16622297 . 10.1385/ENDO:29:1:101 . 8906021 .
• Tannin GM, Agarwal AK, Monder C, New MI, White PC . The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization . The Journal of Biological Chemistry . 266 . 25 . 16653–8 . September 1991 . 10.1016/S0021-9258(18)55351-5 . 1885595 . free .
• Graham DL, Oram JF . Identification and characterization of a high density lipoprotein-binding protein in cell membranes by ligand blotting . The Journal of Biological Chemistry . 262 . 16 . 7439–42 . June 1987 . 10.1016/S0021-9258(18)47584-9 . 3034894 . free .
• Whorwood CB, Mason JI, Ricketts ML, Howie AJ, Stewart PM . Detection of human 11 beta-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase-polymerase chain reaction and localization of the type 2 isoform to renal collecting ducts . Molecular and Cellular Endocrinology . 110 . 1–2 . R7–12 . April 1995 . 7545619 . 10.1016/0303-7207(95)03546-J . 25070635 .
• Mune T, Rogerson FM, Nikkilä H, Agarwal AK, White PC . Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase . Nature Genetics . 10 . 4 . 394–9 . August 1995 . 7670488 . 10.1038/ng0895-394 . 30848352 .
• Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM . Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues . The Journal of Clinical Endocrinology and Metabolism . 83 . 4 . 1325–35 . April 1998 . 10.1210/jcem.83.4.4706 . 9543163 . 10988572 . free .
• Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA . Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL . Journal of Lipid Research . 39 . 4 . 777–88 . April 1998 . 10.1016/S0022-2275(20)32566-9 . 9555943 . free .
• Odermatt A, Arnold P, Stauffer A, Frey BM, Frey FJ . The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane . The Journal of Biological Chemistry . 274 . 40 . 28762–70 . October 1999 . 10497248 . 10.1074/jbc.274.40.28762 . free.
• Sriskanda V, Schwer B, Ho CK, Shuman S . Mutational analysis of Escherichia coli DNA ligase identifies amino acids required for nick-ligation in vitro and for in vivo complementation of the growth of yeast cells deleted for CDC9 and LIG4 . Nucleic Acids Research . 27 . 20 . 3953–63 . October 1999 . 10497258 . 148661 . 10.1093/nar/27.20.3953 .
• Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, Brentzell LM, Watanabe Y, Dixon MJ, Murray JC . A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41 . Genome Research . 10 . 1 . 81–94 . Jan 2000 . 10645953 . 310500 . 10.1101/gr.10.1.81 . 31 January 2024 .
• 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 . 27 . 3 . 375–81 . September 2000 . 10962348 . 10.1016/S8756-3282(00)00344-6 .
• Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, Shih DM, Lusis AJ, Navab M, Fogelman AM . Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids . Arteriosclerosis, Thrombosis, and Vascular Biology . 21 . 4 . 542–7 . April 2001 . 11304470 . 10.1161/01.ATV.21.4.542 . free .
• Pácha J, Lisá V, Miksík I . Effect of cellular differentiation on 11beta-hydroxysteroid dehydrogenase activity in the intestine . Steroids . 67 . 2 . 119–26 . February 2002 . 11755176 . 10.1016/S0039-128X(01)00143-X . 568790 .
• Albertin G, Tortorella C, Malendowicz LK, Aragona F, Neri G, Nussdorfer GG . Human adrenal cortex and aldosterone secreting adenomas express both 11beta-hydroxysteroid dehydrogenase type 1 and type 2 genes . International Journal of Molecular Medicine . 9 . 5 . 495–8 . May 2002 . 11956655 . 10.3892/ijmm.9.5.495 .
• Mazzocchi G, Malendowicz LK, Aragona F, Tortorella C, Gottardo L, Nussdorfer GG . 11beta-Hydroxysteroid dehydrogenase types 1 and 2 are up- and downregulated in cortisol-secreting adrenal adenomas . Journal of Investigative Medicine . 50 . 4 . 288–92 . July 2002 . 12109593 . .

Notes and References

1. Web site: Entrez Gene: HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1.
2. Classen-Houben D, Schuster D, Da Cunha T, Odermatt A, Wolber G, Jordis U, Kueenburg B . Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid . The Journal of Steroid Biochemistry and Molecular Biology . 113 . 3–5 . 248–52 . February 2009 . 19429429 . 10.1016/j.jsbmb.2009.01.009 . 21938309 .
3. Nixon M, Wake DJ, Livingstone DE, Stimson RH, Esteves CL, Seckl JR, Chapman KE, Andrew R, Walker BR . Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. Diabetes . 61 . 4 . 790–6 . April 2012 . 22357964 . 3314355 . 10.2337/db11-0931 .
4. Hintzpeter J, Stapelfeld C, Loerz C, Martin HJ, Maser E . Green tea and one of its constituents, Epigallocatechine-3-gallate, are potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 . PLOS ONE. 9 . 1 . e84468 . 3 January 2014 . 24404164 . 3880318 . 10.1371/journal.pone.0084468 . 2014PLoSO...984468H . free .