ometendoОжирение и метаболизмObesity and metabolism2071-87132306-5524Endocrinology Research Centre10.14341/omet2017248-52ometendo-8791Research ArticleЛекцияLectureОсобенности синтеза, активации и дезактивации глюкокортикоидов. Биологическая роль кортизола в метаболических нарушенияхSynthesis, activation and deactivation of glucocorticoids. The biological role of cortisol in metabolic disordershttps://orcid.org/0000-0002-2232-4765АртемоваЕкатерина ВикторовнаArtemovaEkaterina V.

научный сотрудник отделения "Диабетическая стопа"

MD

profilaktika@bk.ru<p>ФГБУ Эндокринологический научный центр Минздрава России</p>Россия<p>Endocrinology Research Centre</p>Russian Federation2017150920171424852Copyright &#x00A9; Артемова Е.В., 20172017Артемова Е.В.Artemova E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.omet-endojournals.ru/jour/article/view/8791

В свете появляющихся новых данных взгляд на систему гипоталамус-гипофиз-надпочечники-органы-мишени претерпевает значительные изменения, и наряду с механизмом отрицательной обратной связи, возникают предположения о существовании других регуляторных механизмов синтеза, активации и дезактивации ГКС. Тем не менее, в настоящее время имеется сравнительно небольшой объем данных о взаимосвязи между системной и местной продукцией кортизола в тканях. Неуклонный рост числа пациентов с сахарным диабетом (преимущественно 2 типа) и ожирением ставит новые задачи по разработке эффективных лекарственных средств и форм их доставки, методов своевременного выявления и профилактики развития заболевания. Понимание этих процессов позволит создать необходимую научную базу для поиска и разработки новых мишеней для фармакотерапии заболеваний, ассоциированных с нарушением синтеза, активации и действия ГКС.

In the light of the emerging new data, the view of the hypothalamic-pituitary-adrenal-target organs system undergoes significant changes, and along with the negative feedback mechanism, there are suggestions of the existence of other regulatory mechanisms for synthesis, activation, and deactivation of glucocorticosteroids (GCS). However, there is currently a relatively small amount of data on the relationship between systemic and local cortisol production in tissues. The inconsistent increase in the number of patients with diabetes mellitus (predominantly type 2) and obesity poses new challenges in developing effective medicines and their delivery forms, Methods of timely detection and prevention of the development of the disease. Understanding these processes will create the necessary scientific basis for the search and development of new targets for the pharmacotherapy of diseases associated with a violation of synthesis, activation and action of GCS.

Кортизолвненадпочечниковая продукциянеоваскулогенезкардиоваскулярные рискирепарация тканейCortisolvasculogenesiscardiovascular riskstissue repairReferencesRask E, Olsson T, Söderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86(3):1418-1421. doi:10.1210/jc.86.3.1418.Rask E, Olsson T, Söderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86(3):1418-1421. doi:10.1210/jc.86.3.1418.Rask E, Walker BR, Söderberg S, et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: Increased adipose 11β-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab. 2002;87(7):3330-3336. doi:10.1210/jc.87.7.3330.Rask E, Walker BR, Söderberg S, et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: Increased adipose 11β-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab. 2002;87(7):3330-3336. doi:10.1210/jc.87.7.3330.Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88. doi:10.1186/1471-2458-9-88.Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88. doi:10.1186/1471-2458-9-88.Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14:869-881. doi:10.1111/j.1463-1326.2012.01582.x.Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14:869-881. doi:10.1111/j.1463-1326.2012.01582.x.Morgan S a, McCabe EL, Gathercole LL, et al. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A. 2014;111(24):E2482-91. doi:10.1073/pnas.1323681111.Morgan S a, McCabe EL, Gathercole LL, et al. 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A. 2014;111(24):E2482-91. doi:10.1073/pnas.1323681111.Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. Endocr Res. 2002;28(4):449-461. doi:10.1081/ERC-120016822.Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. Endocr Res. 2002;28(4):449-461. doi:10.1081/ERC-120016822.Masuzaki H, Paterson J, Shinyama H, et al. A Transgenic Model of Visceral Obesity and the Metabolic Syndrome. Science (80-). 2001;294(5549):2166-2170. doi:10.1126/science.1066285.Masuzaki H, Paterson J, Shinyama H, et al. A Transgenic Model of Visceral Obesity and the Metabolic Syndrome. Science (80-). 2001;294(5549):2166-2170. doi:10.1126/science.1066285.Wamil M, Seckl JR. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discov Today. 2007;12(13-14):504-520. doi:10.1016/j.drudis.2007.06.001.Wamil M, Seckl JR. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target. Drug Discov Today. 2007;12(13-14):504-520. doi:10.1016/j.drudis.2007.06.001.Joharapurkar A, Dhanesha N, Shah G, Kharul R, Jain M. 11β-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome. Pharmacol Rep. 2012;64(5):1055-1065.Joharapurkar A, Dhanesha N, Shah G, Kharul R, Jain M. 11β-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome. Pharmacol Rep. 2012;64(5):1055-1065.Colao A, Pivonello R, Spiezia S, et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. JClinEndocrinolMetab. 1999;84(0021-972X (Print)):2664-2672.Colao A, Pivonello R, Spiezia S, et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. JClinEndocrinolMetab. 1999;84(0021-972X (Print)):2664-2672.Sharma ST, Nieman LK, Feelders RA. Comorbidities in Cushing’s disease. Pituitary. 2015;18(2):188-194. doi:10.1007/s11102-015-0645-6.Sharma ST, Nieman LK, Feelders RA. Comorbidities in Cushing’s disease. Pituitary. 2015;18(2):188-194. doi:10.1007/s11102-015-0645-6.Espinosa-de-Los-Monteros AL, Sosa E, Martinez N, Mercado M. Persistence of Cushing’s disease symptoms and comorbidities after surgical cure: a long-term, integral evaluation. Endocr Pract. 2013;19(2):252-258. doi:10.4158/EP12247.OR [doi].Espinosa-de-Los-Monteros AL, Sosa E, Martinez N, Mercado M. Persistence of Cushing’s disease symptoms and comorbidities after surgical cure: a long-term, integral evaluation. Endocr Pract. 2013;19(2):252-258. doi:10.4158/EP12247.OR [doi].Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol. 2006;59(1):15-26. doi:10.1016/j.critrevonc.2005.12.003.Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol. 2006;59(1):15-26. doi:10.1016/j.critrevonc.2005.12.003.Webb JD, Coleman ML, Pugh CW. Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci. 2009;66(22):3539-3554. doi:10.1007/s00018-009-0147-7.Webb JD, Coleman ML, Pugh CW. Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci. 2009;66(22):3539-3554. doi:10.1007/s00018-009-0147-7.Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn E a. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549-580. doi:10.1124/pr.56.4.3.549.Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn E a. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549-580. doi:10.1124/pr.56.4.3.549.Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(2007):2003-2012. doi:10.1016/j.cellsig.2007.05.013.Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(2007):2003-2012. doi:10.1016/j.cellsig.2007.05.013.Oka T, Morita H, Komuro I. Novel molecular mechanisms and regeneration therapy for heart failure. J Mol Cell Cardiol. 2016;92:46-51. doi:10.1016/j.yjmcc.2016.01.028.Oka T, Morita H, Komuro I. Novel molecular mechanisms and regeneration therapy for heart failure. J Mol Cell Cardiol. 2016;92:46-51. doi:10.1016/j.yjmcc.2016.01.028.Matsuda S, Gomi F, Oshima Y, Tohyama M, Tano Y. Vascular endothelial growth factor reduced and connective tissue growth factor induced by triamcinolone in ARPE19 cells under oxidative stress. Invest Ophthalmol Vis Sci. 2005;46(3):1062-1068.Matsuda S, Gomi F, Oshima Y, Tohyama M, Tano Y. Vascular endothelial growth factor reduced and connective tissue growth factor induced by triamcinolone in ARPE19 cells under oxidative stress. Invest Ophthalmol Vis Sci. 2005;46(3):1062-1068.Rao R, Redha R, Macias-Perez I, et al. Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo. J Biol Chem. 2007;282(23):16959-16968. doi:10.1074/jbc.M701214200.Rao R, Redha R, Macias-Perez I, et al. Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo. J Biol Chem. 2007;282(23):16959-16968. doi:10.1074/jbc.M701214200.Logie JJ, Ali S, Marshall KM, Heck MMS, Walker BR, Hadoke PWF. Glucocorticoid-mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration. PLoS One. 2010;5(12). doi:10.1371/journal.pone.0014476.Logie JJ, Ali S, Marshall KM, Heck MMS, Walker BR, Hadoke PWF. Glucocorticoid-mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration. PLoS One. 2010;5(12). doi:10.1371/journal.pone.0014476.Slominski A, Zbytek B, Nikolakis G, et al. Steroidogenesis in the skin: implications for local immune functions. J Steroid Biochem Mol Biol. 2013;137:107-123. doi:10.1016/j.jsbmb.2013.02.006.Slominski A, Zbytek B, Nikolakis G, et al. Steroidogenesis in the skin: implications for local immune functions. J Steroid Biochem Mol Biol. 2013;137:107-123. doi:10.1016/j.jsbmb.2013.02.006.Cirillo N, Prime SS. Keratinocytes synthesize and activate cortisol. J Cell Biochem. 2011;112(6):1499-1505. doi:10.1002/jcb.23081.Cirillo N, Prime SS. Keratinocytes synthesize and activate cortisol. J Cell Biochem. 2011;112(6):1499-1505. doi:10.1002/jcb.23081.Slominski A, Wortsman J, Kohn L, et al. Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin. J Invest Dermatol. 2002;119(6):1449-1455. doi:10.1046/j.1523-1747.2002.19617.x.Slominski A, Wortsman J, Kohn L, et al. Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin. J Invest Dermatol. 2002;119(6):1449-1455. doi:10.1046/j.1523-1747.2002.19617.x.Jamora C, DasGupta R, Kocieniewski P, Fuchs E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature. 2003;422(6929):317-322. doi:10.1038/nature01893.Jamora C, DasGupta R, Kocieniewski P, Fuchs E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature. 2003;422(6929):317-322. doi:10.1038/nature01893.Slominski A, Malarkey WB, Wortsman J, Asa SL, Carlson A. Human skin expresses growth hormone but not the prolactin gene. J Lab Clin Med. 2000;136(6):476-481. doi:10.1067/mlc.2000.110605.Slominski A, Malarkey WB, Wortsman J, Asa SL, Carlson A. Human skin expresses growth hormone but not the prolactin gene. J Lab Clin Med. 2000;136(6):476-481. doi:10.1067/mlc.2000.110605.Kono M, Nagata H, Umemura S, Kawana S, Osamura RY. In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin. FASEB J. 2001;15(12):2297-2299. doi:10.1096/fj.01-0254fje.Kono M, Nagata H, Umemura S, Kawana S, Osamura RY. In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin. FASEB J. 2001;15(12):2297-2299. doi:10.1096/fj.01-0254fje.Kauser S, Slominski A, Wei ET, Tobin DJ. Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. FASEB J. 2006;20(7):882-895. doi:10.1096/fj.05-5257com.Kauser S, Slominski A, Wei ET, Tobin DJ. Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. FASEB J. 2006;20(7):882-895. doi:10.1096/fj.05-5257com.Slominski AT, Manna PR, Tuckey RC. Cutaneous glucocorticosteroidogenesis: Securing local homeostasis and the skin integrity. Exp Dermatol. 2014;23(6):369-374. doi:10.1111/exd.12376.Slominski AT, Manna PR, Tuckey RC. Cutaneous glucocorticosteroidogenesis: Securing local homeostasis and the skin integrity. Exp Dermatol. 2014;23(6):369-374. doi:10.1111/exd.12376.Redvers RP, Li A, Kaur P. Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci U S A. 2006;103(35):13168-13173. doi:10.1073/pnas.0602579103.Redvers RP, Li A, Kaur P. Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc Natl Acad Sci U S A. 2006;103(35):13168-13173. doi:10.1073/pnas.0602579103.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):10265-10275. doi:10.1074/jbc.M110.188268.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):10265-10275. doi:10.1074/jbc.M110.188268.Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in Wound Healing: A Comprehensive Review. Adv wound care. 2014;3(7):445-464. doi:10.1089/wound.2013.0473.Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in Wound Healing: A Comprehensive Review. Adv wound care. 2014;3(7):445-464. doi:10.1089/wound.2013.0473.Shi Y, Shu B, Yang R, et al. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6(1):120. doi:10.1186/s13287-015-0103-4.Shi Y, Shu B, Yang R, et al. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6(1):120. doi:10.1186/s13287-015-0103-4.

The authors declare that there are no conflicts of interest present.