References

nogr

Экспериментальная и клиническая гастроэнтерология

Experimental and Clinical Gastroenterology

1682-8658

«Global Media Technologies»

nogr-293

Research Article

ПЕРЕДОВАЯ СТАТЬЯ

LEADING ARTICLE

ПАТОФИЗИОЛОГИЧЕСКИЕ АСПЕКТЫ ПЛЕЙОТРОПНЫХ ЭФФЕКТОВ ГАСТРОИНТЕСТИНАЛЬНЫХ ГОРМОНОВ

PATHOPHYSIOLOGICAL ASPECTS OF PLEIOTROPIC EFF ECTS OF GASTROINTESTINAL HORMONES

Корнюшин

О. В.

Korniushyn

O. V.

o.kornyushin@gmail.com

Торопова

Я. Г.

Toropova

J. G.

noemail@neicon.ru

Семикова

Г. В.

Semikova

G. V.

noemail@neicon.ru

Неймарк

А. Е.

Neimark

A. E.

noemail@neicon.ru

Дора

С. В.

Dora

S. V.

noemail@neicon.ru

Давыдова

Е. Е.

Davidova

E. E.

noemail@neicon.ru

Карелли

Л. ..

Carelli

L. ..

noemail@neicon.ru

Ткачук

О. В.

Tkachuk

O. V.

noemail@neicon.ru

Маркитантова

А. С.

Markitantova

A. S.

noemail@neicon.ru

ФГБУ «Северо-Западный федеральный медицинский исследовательский центр имени В. А. Алмазова» Министерства здравоохранения Российской ФедерацииРоссияNorth-West medical research centre named V. A. Almazov Ministry of health of RussiaRussian Federation

Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова МЗ РФРоссияFirst St. Petersburg state medical University named Acad. I. P. PavlovaRussian Federation

ФГБУ «Северо-Западный федеральный медицинский исследовательский центр имени В. А. Алмазова» Министерства здравоохранения Российской Федерации; Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова МЗ РФРоссияNorth-West medical research centre named V. A. Almazov Ministry of health of Russia; First St. Petersburg state medical University named Acad. I. P. PavlovaRussian Federation

Санкт-Петербургский политехнический университет Петра ВеликогоРоссияPeter the Great St. Petersburg Polytechnic UniversityRussian Federation

2016

20102016

010414

2016

Корнюшин О.В., Торопова Я.Г., Семикова Г.В., Неймарк А.Е., Дора С.В., Давыдова Е.Е., Карелли Л..., Ткачук О.В., Маркитантова А.С.

Korniushyn O.V., Toropova J.G., Semikova G.V., Neimark A.E., Dora S.V., Davidova E.E., Carelli L..., Tkachuk O.V., Markitantova A.S.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.nogr.org/jour/article/view/293

Уникальные свойства и большой терапевтический потенциал инкретиновых препаратов позволили им за беспрецедентно короткий срок завоевать прочное место в современных алгоритмах лечения СД 2 типа. В связи с открытием инкретинового эффекта и введением в клиническую практику инкретиномиметиков возрос интерес исследователей к изучению плейотропных эффектов гормонов ЖКТ. В экспериментальных и клинических исследованиях последних лет показаны цитопротективные и цитопролиферативные эффекты ряда интестинальных гормонов, а именно глюкагон-подобного пептида-1 (ГПП-1), грелина (Гр), обестатина при их системном введении. В обзоре представлен анализ имеющихся на сегодняшний день результатов фундаментальных и клинических исследований, посвященных изучению плейотропного потенциала гастроинтестинальных пептидов, а также определена актуальность дальнейших исследований по изучению метаболических эффектов бариатрических операций.

The unique properties and a great therapeutic potential of incretin drugs allowed them to win a firm place in modern algorithms of treatment of type 2 diabetes in an unprecedented short period of time. Due to discovery of the incretin effect and introduction of the incretin mimetics into clinical practice, an interest of the researchers was growing to study the pleiotropic effects of gastrointestinal hormones. In experimental and clinical studies in recent years there has been shown the cytoprotective and cytoproliferative effects of a number of intestinal hormones, namely glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin when administered systemically. This review presents an analysis of the currently available results of fundamental and clinical research on the pleiotropic potential of the gastrointestinal peptides, and also determines the relevance of further research on the metabolic effects of bariatric surgery.

глюкагон-подобный пептид-1грелинобестатинкардиопротекциянейропротекциянеалкогольная жировая болезнь печенибариатрическая хирургия

glucagon-like peptide-1ghrelinobestatincardioprotectionneuroprotectionnon-alcoholic fatty liver diseasebariatric surgery

References1

Ban K., Noyan-Ashraf M.H., Hoefer J. et аl. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptordependent and -independent pathways. Circulation, 2008, 117, pp. 2340-50.

Pyke C., Heller R. S., Kirk R. K. et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology, 2014, 155, pp. 1280-90.

Perry T., Lahiri D. K., Sambamurti K. et аl. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res, 2003, vol. 72, no 5, pp. 603-12.

Gupta N. A., Mells J., Dunham R. M. et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology, 2010, 51, pp. 1584-1592.

Cao J. M., Ong H., Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab, 2006, 17, pp. 13-8.

Papotti M., Ghè C., Cassoni P., et al. Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab, 2000, no. 85, pp. 3803-7.

Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. CardiovascRes, 2006, no. 69, pp. 227-35.

Granata R., Settanni F., Gallo D. et al. Obestatin promotes survival of pancreatic beta-cells and human islets and induces expression of genes involved in the regulation of beta-cell mass and function. Diabetes, 2008, no. 57, pp. 967-979.

Han L., Yu Y., Sun X., Wang B. Exendin-4 directly improves endothelial dysfunction in isolated aortas from obese rats through the cAMP or AMPK-eNOS pathways. Diabetes research and clinical practice, 2012, vol. 97, no. 3, pp. 453-60.

Sélley E., Kun I., Szijártó A. et al. Vasodilator Effect of Glucagon: Receptorial Crosstalk Among Glucagon, GLP-1, and Receptor for Glucagon and GLP-1. Horm Metab Res, 2016, vol. 48, no. 7, pp 476-483.

Ussher J. R., Drucker D. J. Cardiovascular biology of the incretin system. Endocr Rev, 2012, no. 33, pp. 187-215.

Sélley E., Kun S., Szijártó I. A. et al. Exenatide induces aortic vasodilation increasing hydrogensulphide, carbonmonoxide and nitric oxide production. Cardiovasc Diabetol, 2014, no. 13, pp. 69.

Richter G., Feddersen O., Wagner U. et al. GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery. Am J Physiol, 1993, no. 265, pp. 374-381.

Green B. D., Hand K. V., Dougan J. E. et al. GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. Arch Biochem Biophys, 2008, no. 478, pp. 136-142.

Ban K., Noyan-Ashraf M.H., Hoefer J. et al. Cardioprotective and vasodilatory actions of glucagonlike peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation, 2008, no. 117, pp. 2340-50.

Erdogdu O., Nathanson D., Sjoholm A. et al. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol, 2010, no. 325, pp. 26-35.

Erdogdu O., Eriksson L., Xu H. et al. Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol, 2013, no. 50, pp. 229-41.

Nathanson D., Erdogdu O., Pernow J. et al. Endothelial dysfunction induced by triglycerides is not restored by exenatide in rat conduit arteries ex vivo. Regul Pept, 2009, no. 157, pp. 8-13.

Ishibashi Y., Matsui T., Takeuchi M., Yamagishi S. Glucagonlike peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun, 2010, no. 391, pp. 1405-1408.

Ishibashi Y., Matsui T., Takeuchi M., Yamagishi S. Sitagliptin augments protective effects of GLP-1 against advanced glycation end product receptor axis in endothelial cells. Horm. Metab, 2011, no. 43, pp. 731-734.

Chai W., Dong Z., Wang N. et al. Glucagonlike peptide 1 recruits microvasulature and increases glucose use in microvasculature and increases glucose use in muscle via nitric oxidedependent mechanism. Diabetes, 2012, no. 61, pp. 888-896.

Nagashima M., Watanabe T., Terasaki M. et al. Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia, 2011; no. 54, pp. 2649-59.

Li X. C., Zhuo J. L. Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: theory versus promise. Clin Sci, 2007, no. 113, pp. 183-193.

Nystrom T., Gutniak M. K., Zhang Q. et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. American journal of physiology Endocrinology and metabolism, 2004, vol. 287, no. 6, pp. 1209-15.

Torimoto K., Okada Y., Mori H., Otsuka T. Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovascular Diabetology, 2015, no. 14, pp. 25.

Tremblay A. J., Lamarche B., Deacon C. F. et al. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism, 2014, no. 63, pp 1141-8.

Rizzo M., Chandalia M., Patti A. M. et al. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol, 2014, no. 13, pp 49.

Wang X. H., Han L. N., Yu Y. R. et al. Effects of GLP-1 Agonist Exenatide on Cardiac Diastolic Function and Vascular Endothelial Function in Diabetic Patients. Sichuan Da Xue Xue Bao Yi Xue Ban, 2015, vol. 46, no. 4, pp. 586-90.

Dai Y., Mehta J. L., Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther, 2013, no. 27, pp. 371-380.

Hattori Y., Jojima T., Tomizawa A. et al. A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia, 2010, no. 53, pp. 2256-2263.

Gaspari T., Liu H., Welungoda I. et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diabetes & vascular disease research: official journal of the International Society of Diabetes and Vascular Disease, 2011, vol. 8, no. 2, pp. 117-24.

Krasner N. M., Ido Y., Ruderman N. B. et al. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One, 2014, no. 9, pp. 97554.

Liu L., Liu J., Wong W. T. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension, 2012, no. 60, pp. 833-841.

Liu H., Dear A. E., Knudsen L. B., Simpson R. W. A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol, 2009, no. 201, pp. 59-66.

Shiraki A., Oyama J., Komoda H., et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-alpha-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis, 2012, vol. 221, pp. 375-82.

Batchuluun B., Inoguchi T., Sonoda N. et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis, 2014, no. 232, pp. 156-64.

Schisano B., Harte A. L., Lois K. et al. GLP-1 analogue, Liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul Pept, 2012, no. 174, pp/. 46-52.

Tang, S., Zhang, Q., Tang, H. et al. Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways. Endocrine, 2016, no. 53, pp. 107.

Panjwani N., Mulvihill E. E., Longuet C. et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(_/_) mice. Endocrinology, 2013, no. 154, pp. 127-39.

Virdis A., Duranti E., Colucci R. et al. Ghrelin restores nitric oxide availability in resistance circulation of essential hypertensive patients: role of nad(p)h oxidase. Eur Heart J, 2015, no. 36, pp. 3023-3030.

Tesauro M., Schinzari F., Iantorno M., et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation, 2005, no. 112, pp. 2986-92.

Tesauro M., Schinzari F., Rovella V., et al. Ghrelin restores the endothelin-1/nitric oxide balance in patients with obesity-related metabolic syndrome. Hypertension, 2009, no. 11, pp. 995-1000.

Yano Y., Nakazato M., Toshinai K. et al. Circulating des-acyl ghrelin improves cardiovascular risk prediction in older hypertensive patients. Am J Hypertens, 2014, no. 27, pp. 727-733.

Isgaard J., Barlind A., Johansson I. Cardiovascular effects of ghrelin and growth hormone secretagogues. Cardiovasc Hematol Disord Drug Targets, 2008, no. 8, pp. 133-7.

Nagaya N., Koijma M., Uematsu M. et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol, 2001, no. 280, pp. 1483-7.

Henriques-Coelho T., Correia-Pinto J., Roncon-Albuquerque Jr. R. et al. Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol, 2004, no. 287, pp. 2885-2890.

Anderwald-Stadler M., Krebs M., Promintzer M. et al. Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans. Am J Physiol Endocrinol Metab, 2007, no. 293, pp. 1393-1398.

Li Z. F., Guo Z. F., Yang S. G. et al. Circulating ghrelin and ghrelin to obestatin ratio are low in patients with untreated mild-to-moderate hypertension. Regul Pept, 2010, no. 165, pp. 206-209.

Wang W. M., Li S. M., Du F. M. et al. Ghrelin and obestatin levels in hypertensive obese patients. J Int Med Res, 2014, no. 42, pp. 1202-1208.

Li Z. F., Zhou D. X., Pan W. Z., et al. Circulating ghrelin was negatively correlated with pulmonary arterial pressure in atrial septal defect patients. Chin Med J, 2013, no. 126, pp. 3936-3939.

Ren A. J., He Q., Shi J. S. et al. Association of obestatin with blood pressure in the third trimesters of pregnancy. Peptides, 2009, no. 30, pp. 1742-1745.

Shao L., Zhao Y. T., Teng L. L. et al. Circulating obestatin levels correlate with fasting insulin and HOMA-IR but not with hypertension in elderly men. Cell Biochem Biophys, 2014, no. 69, pp. 89-92.

Li Z. F., Song S. W., Qin Y. W. et al. Bolus intravenous injection of obestatin does not change blood pressure level of spontaneously hypertensive rat. Peptides, 2009, no. 30, pp. 1928-1930.

Broglio F., Gottero C., Prodam F. et al. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab, 2004, no. 89, pp. 3062-5.

Moazed B., Quest D., Gopalakrishnan V. Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels. Eur J Pharmacol, 2009, no. 604, pp. 79-86.

Ku J., Andrews Z. B., Barsby T. et al. Ghrelinrelated peptides exert protective effects in the cerebral circulation of male mice through a non-classical ghrelin receptor(s). Endocrinology, 2015, no. 156, pp. 280-290.

Okumura H., Nagaya N., Enomoto M. Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol, 2002, no. 39, pp. 779-783.

Yang D., Liu Z., Zhang H., Luo Q. Ghrelin protects human pulmonary artery endothelial cells against hypoxia-induced injury via PI3-kinase/Akt. Peptides, 2013, no. 42, pp. 112-117.

Grossini E., Raina G., Farruggio S. Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs. Endocrinology, 2016, vol. 157, no. 6, pp. 2403-15.

Iantorno M., Chen H., Kim J. A. et al. Ghrelin has novel vascular actions that mimic pi 3-kinase-dependent actions of insulin to stimulate production of no from endothelial cells. Am J Physiol Endocrinol Metab. 2007, no. 292, pp. 756-764.

Wiley K. E., Davenport A. P. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol. 2002, no. 136, pp. 1146-52.

Baldanzi G., Filigheddu N., Cutrupi S. et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/ AKT. J Cell Biol 2002, no. 159, pp. 1029-37.

Kleinz M. J., Maguire J. J., Skepper J. N., Davenport A. P. Functional andimmunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res, 2006, no. 69, pp. 227-235.

Li P., Liu Y., Xiang Y. et al. Ghrelin protects human umbilical vein endothelial cells against advanced glycation end products-induced apoptosis via NO/cGMP signaling. Int J Clin Exp Med, 2015, vol. 8, no. 9, pp. 15269-15275.

Kawczynska-Drozdz A., Olszanecki R., Jawien J. et al. Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens, 2006, no. 19, pp. 764-767.

Chen X., Chen Q., Wang L., Li G. Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells. Metabolism, 2013, vol. 62, no. 5, pp. 743-752.

Kellokoski E., Kunnari A., Jokela M. et al. Ghrelin and obestatin modulate early atherogenic processes on cells: enhancement of monocyte adhesion and oxidized lowdensity lipoprotein binding. Metabolism, 2009, no. 58, pp. 1572-1580.

Favaro E., Granata R., Miceli I. et al. The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways. Diabetologia, 2012, no. 55, pp. 1058-1070.

Agnew A. J., Robinson E., McVicar C.M. et al. The gastrointestinal peptide obestatin induces vascular relaxation via specific activation of endothelium-dependent NO signalling. Br J Pharmacol, 2012, no. 166, pp. 327-338.

Ku J. M., Andrews Z. B., Barsby T. et al. Ghrelin-related peptides exert protective effects in the cerebral circulation of male mice through a nonclassical ghrelin receptor(s). Endocrinology, 2015, no. 156, pp. 280-290.

Schinzari F., Iantorno M., Campia U. et al. Vasodilator responses and endothelin-dependant vasoconstriction in metabolically healthy obesity and the metabolic syndrome. Am J Physiol Endocrinol Metab 2015, no. 309, pp. 787-792.

Gurriarán-Rodríguez U., Santos-Zas I., González-Sánchez J. et al. Action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling. Mol Ther, 2015, no. 6, pp. 1003-1021.

Robinson E., Cassidy R. S., Tate M. et al. Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Res Cardiol, 2015, no. 110, pp. 20.

Tate M., Robinson E., Green B. D. et al. Exendin-4 attenuates adverse cardiac remodelling in streptozotocininduced diabetes via specific actions on infiltrating macrophages. Basic Res Cardiol, 2016, vol. 111, pp. 1.

Perry T., Lahiri D. K., Sambamurti K. et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res, 2003, vol. 72, no. 5, pp. 603-12.

Teramoto S., Miyamoto N., Yatomi K. et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, providesneuroprotection in mice transient focal cerebral ischemia. J Cereb Blood Flow Metab, 2011, vol. 31, no. 8, pp. 1696-705.

Chen F., Wang W., Ding H. et al. The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia. J Neuroinflammation, 2016, vol. 26, no. 13, pp. 204.

Marso S. P., Bain S. C., Consoli A. et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2Diabetes. N Engl J Med, 2016, no. 15.

Brywe K. G., Leverin A. L., Gustavsson M. Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation. Endocrinology, 2005, vol. 146, no. 11, pp. 4665-72.

Liu Y., Wang P. S., Xie D. et al. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chin J Physiol, 2006, vol. 31, no. 5, pp. 244-50.

Andrews Z. B., Erion D., Beiler R. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci, 2009, vol. 11, no. 29(45), pp. 14057-65.

Chung H., Seo S., Moon M., Park S. Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol. 2008, vol. 198, no. 3, pp. 511-21.

Lopez N. E., Gaston L., Lopez K. R. et al. Early ghrelin treatment attenuates disruption of the blood brain barrier and apoptosis after traumatic brain injury through a UCP-2 mechanism. Brain Res, 2012, vol. 13, no. 1489, pp. 140-8.

Cheyuo C., Wu R., Zhou M. et al. Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve. Shock, 2011, vol. 35, no. 3, pp. 258-65.

Brunt E. M. Nonalcoholic steatohepatiatis. Semin Liver Dis, 2004, vol. 24, pp. 3-20.

Marchesini G, Brizi M, Bianchi G. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes, 2001, vol. 50, pp. 1844-50.

Turton M. D., O’Shea D., Gunn I. et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996, no. 379, pp. 69-72.

Svegliati-Baroni G., Saccomanno S., Rychlicki C. et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int, 2011, no. 31, pp. 1285-1297.

Lee Y. S., Shin S., Shigihara T. et al. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes, 2007, no. 56, pp. 1671-1679.

Ben-Shlomo S., Zvibel I., Shnell M. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol, 2011, vol. 54, no. 6, pp. 1214-23.

Fisher F. M., Chui P. C., Antonellis P. J. et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes, 2010, vol. 59, no. 11, pp. 2781-9.

Li L., Miao Z., Liu R. et al. Liraglutide prevents hypoadiponectinemia-induced insulin resistance and alterations of gene expression involved in glucose and lipid metabolism. Mol Med, 2011, no. 17, pp. 1168-1178.

Zhang L., Yang M., Ren H. et al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int, 2013, no. 33, pp. 794-804.

Ding X., Saxena N. K., Lin S. et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006, no. 43, pp. 173-181.

Yamamoto T., Nakade Y., Yamauchi T. et al. Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice. World J Gastroenterol, 2016, vol. 28, no. 22(8), pp. 2512-23.

D’Alessio D.A., Kahn S. E., Leusner C. R. et al. Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest, 1994, no. 93, pp. 2263-2266.

Zander M., Madsbad S., Madsen J. L. et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet, 2002, no. 359, pp. 824-830.

Cuthbertson D. J., Irwin A., Gardner C. J. et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One, 2012, vol. 7, pp. 50117.

100

Armstrong M. J., Houlihan D. D., Rowe I. A. et al. Safety and efﬁcacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther, 2013, no. 37, pp. 234-242.

101

Tushuizen M. E., Bunck M. C., Pouwels P. J. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int, 2006, no. 26, pp. 1015-1017.

102

García Díaz E., Guagnozzi D., Gutiérrez V. et al. Effect of incretin therapies compared to pioglitazone and gliclazide in non-alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study. Endocrinol Nutr, 2016, vol. 63, no. 5, pp. 194-201.

103

Armstrong M. J., Barton D., Gaunt P. et al. Liraglutide efﬁcacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial. BMJ Open 2013, vol. 4, no. 3(11), pp. 003995.

104

Armstrong M. J., Hull D., Guo K. et al. Glucagon-like peptide 1 decreases lipotoxicity in nonalcoholic steatohepatitis. J Hepatol. 2016, vol. 64, no. 2, pp. 399-408.

105

Marchesini G., Pagotto U., Bugianesi E. et al. Low ghrelin concentrations in nonalcoholic fatty liver disease arerelated to insulin resistance. J Clin Endocrinol Metab, 2003, vol. 88, no. 12, pp. 5674-9.

106

Gutierrez-Grobe Y., Villalobos-Blasquez I., Sánchez-Lara K., et al. High ghrelin and obestatin levels and low risk of developing fatty liver. Ann Hepatol, 2010, vol. 9, no. 1, pp. 52-7.

107

Aktas B., Yilmaz Y., Eren F. et al. Serum levels of vaspin, obestatin, and apelin-36 in patients with nonalcoholicfatty liver disease. Metabolism, 2011, vol. 60, no. 4, pp. 544-9.

108

Aydin S. Is it appropriate to study blood ghrelin and obestatin in non-alcoholicfatty liver disease (NAFLD) without using protease inhibitors? Ann Hepatol. 2012, vol. 11, no. 1, pp. 145-6.

109

Estep M., Abawi M., Jarrar M. et al. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non-alcoholic fatty liver disease. Obes Surg, 2011, no. 1, pp. 1750-7.

110

Mykhalchyshyn G., Kobyliak N., Bodnar P. Diagnostic accuracy of acyl-ghrelin and it association with non-alcoholic fatty liver disease in type 2 diabetic patients. J Diabetes Metab Disord, 2015, vol. 19, no. 14, pp. 44.

111

Zhao T. J., Liang G., Li R. L. et al. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA, 2010, no. 107, pp. 7467-7472.

112

Li Y., Hai J., Li L. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine, 2013, vol. 43, no. 2, pp. 376-86.

113

Waseem T., Duxbury M., Ito H., et al. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery, 2008, no. 143, pp. 334-342.

114

Cetin E., Kanbur M., Cetin N. et al. Hepatoprotective effect of ghrelin on carbon tetrachloride-induced acute liver injury in rats. Regul Pept, 2011, no. 171, pp. 1-5.

115

Franz MJ, VanWormer JJ, Craiin AL, et al. Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc, 2007, vol. 107, no. 10, pp. 1755-67.

116

Buchwald H., Avidor Y., Braunwald E. et al. Bariatric surgery: a systematic review and meta-analysis. JAMA, 2004, vol. 292, no. 14, pp. 1724-1737.

117

Торопова Я. Г., Корнюшин О. В., Полуничева Е. В. и соавт. Кардиотропные эффекты гастроинтестинальных гормонов у пациентов с метаболическим синдромом после бариатрических операций. Российский физиологический журнал им. И. М. Сеченова, 2016, № 1, С. 100-112.

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