Генетические аспекты неалкогольной жировой болезни печени
Аннотация
Неалкогольная жировая болезнь печени (НАЖБП) является наиболее часто диагностируемой патологией этого органа. Наблюдается увеличение доли случаев НАЖБП в структуре заболеваний печени у детей и подростков, что напрямую связано с ростом распространенности ожирения. Спектр изменений печеночной ткани при НАЖБП варьирует от доброкачественного стеатоза гепатоцитов до неалкогольного стеатогепатита, фиброза, цирроза печени и гепатоцеллюлярной карциномы. С ростом распространенности НАЖБП у детей мы можем ожидать увеличение числа случаев неблагоприятных исходов среди лиц трудоспособного возраста. Ключевой проблемой НАЖБП остается прогнозирование исходов заболевания. В эпидемиологических и генетических исследованиях показана связь морфологической стадии НАЖБП и наследственных факторов. В настоящее время выделяют три гена, ассоциированных с НАЖБП (PNPLA3, TM6SF2 и GCKR), которые вместе с генами, отвечающими за инсулинорезистентность, депонирование липидов, воспаление и фиброгенез в гепатоцитах, определяют фенотип жировой болезни печени. Предложено современное понимание вопросов генетики, развития стеатоза печени и прогрессирования неалкогольного стеатогепатита. Ожидается, что эти знания могут трансформировать наши стратегии по стратификации риска у пациентов с НАЖБП и способствовать выявлению новых терапевтических целей.
Об авторах
П. О. Богомолов
Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского
Россия
Раскрытие интересов:
Россия
кандидат медицинских наук, заведующий гепатологическим отделом
129110, Москва, ул. Щепкина, д. 61/2, кор. 1,
+7 (499) 674-07-09,
Раскрытие интересов:
Авторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить
К. Ю. Кокина
Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского
Россия
Раскрытие интересов:
Россия
Раскрытие интересов:
Авторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить
А. Ю. Майоров
Национальный медицинский исследовательский центр эндокринологии
Россия
Раскрытие интересов:
Россия
Раскрытие интересов:
Авторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить
Е. Е. Мишина
Национальный медицинский исследовательский центр эндокринологии
Россия
Раскрытие интересов:
Россия
Раскрытие интересов:
Авторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить
Список литературы
1. Sanyal AJ. NASH: A global health problem. Hepatol Res. 2011; 41(7):670–674. doi: 10.1111/j.1872-034X.2011.00824.
2. Chalasani N, Younossi Y, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005–2023. doi: 10.1002/hep.25762.
3. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431. Epub 2016 Feb 22.
4. Drapkina OM, Ivashkin VT. Liver disease structure explored in Russian Federation: national-wide DIREG-L-01903 study for non-alcoholic fatty liver disease screening. J Hepatol. 2011;54 Suppl 1:332. doi: 10.1016/s0168-8278(11)60832-5.
5. Ивашкин В.Т., Драпкина О.М., Маев И.В., и др. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в Российской Федерации: результаты исследования DIREG 2 // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. — 2015. — Т. 25. — № 6 — С. 31–41.
6. Drapkina O, Evsyutina Y, Ivashkin V. Prevalence of non-alcoholic fatty liver disease in the Russian Federation: the open, multicenter, prospective study, DIREG 1. American Journal of Clinical Medicine Research. 2015;3(2):31–36. doi: 10.12691/ajcmr-3-2-3.
7. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–555. doi: 10.1053/j.gastro.2014.11.039.
8. Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19(29):5219–5238. doi: 10.2174/13816128113199990381.
9. Guerrero R, Vega GL, Grundy SM, et al. Ethnic differences in hepatic steatosis: an insulin resistance paradox. Hepatology. 2009; 49(3):791–801. doi: 10.1002/hep.22726.
10. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–1395. doi: 10.1002/hep.20466.
11. Schwimmer JB, Celedon MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5): 1585–1592. doi: 10.1053/j.gastro.2009.01.050.
12. Makkonen J, Pietilainen KH, Rissanen A, et al. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol. 2009;50(5):1035–1042. doi: 10.1016/j.jhep.2008.12.025.
13. Loomba R, Schork N, Chen CH, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–1793. doi: 10.1053/j.gastro.2015.08.011.
14. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–1465. doi: 10.1038/ng.257.
15. Singal AG, Manjunath H, Yopp AC, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109(3):325–334. doi: 10.1038/ajg.2013.476.
16. Valenti L, Al-Serri A, Daly AK, et al. Homozygosity, for the patatinlike phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–1217. doi: 10.1002/hep.23622.
17. Huang Y, He S, Li JZ, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107(17): 7892–7897. doi: 10.1073/pnas.1003585107.
18. Basantani MK, Sitnick MT, Cai L, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. Lipid Res. 2011;52(2):318–329. doi: 10.1194/jlr.M011205.
19. Kumari M, Schoiswohl G, Chitraju C, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012;15(5):691–702. doi: 10.1016/j.cmet.2012.04.008.
20. Pingitore P, Pirazzi C, Mancina RM, et al. Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta. 2014;1841(4): 574–580. doi: 10.1016/j.bbalip.2013.12.006.
21. Chen W, Chang B, Li L, Chan L. Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology. 2010;52(3):1134–1142. doi: 10.1002/hep.23812.
22. He S, McPhaul C, Li JZ, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–6715. doi: 10.1074/jbc.M109.064501.
23. Smagris E, BasuRay S, Li J, et al. Pnpla3 I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61(1):108–118. doi: 10.1002/hep.27242.
24. Donati B, Motta BM, Pingitore P, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016;63(3):787–798. doi: 10.1002/hep.28370.
25. Bruschi FV, Claudel T, Tardelli M, et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology. 2017;65(6):1875–1890. doi: 10.1002/hep.29041.
26. Trepo E, Nahon P, Bontempi G, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology. 2014;59(6):2170–2177. doi: 10.1002/hep.26767.
27. Hyysalo J, Mannisto VT, Zhou Y, et al. A population-based study on the prevalence of NASH using scores validated against liver histology. J Hepatol. 2014;60(4):839–846. doi: 10.1016/j.jhep.2013.12.009.
28. Valenti L, Rumi M, Galmozzi E, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53(3):791–799. doi: 10.1002/hep.24123.
29. Valenti L, Motta BM, Soardo G, et al. PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PLoS One. 2013;8(10):e75982. doi: 10.1371/journal.pone.0075982.
30. Kozlitina J, Smagris E, Stender S, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–356. doi: 10.1038/ng.2901.
31. Petta S, Miele L, Bugianesi E, et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in nonalcoholic fatty liver disease. PLoS One. 2014;9(2):e87523. doi: 10.1371/journal.pone.0087523.
32. Mahdessian H, Taxiarchis A, Popov S, et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A. 2014;111(24): 8913–8918. doi: 10.1073/pnas.1323785111.
33. Liu YL, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with nonalcoholic fatty liver disease. Nat Commun. 2014;5:4309. doi: 10.1038/ncomms5309.
34. Milano M, Aghemo A, Mancina RM, et al. Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients. Hepatology. 2015;62(1): 111–117. doi: 10.1002/hep.27811.
35. Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol. 2015;26(2):88–95. doi: 10.1097/MOL.0000000000000155.
36. Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324. doi: 10.1371/journal.pgen.1001324.
37. Beer NL, Tribble ND, McCulloch LJ, et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet. 2009;18(21):4081–4088. doi: 10.1093/hmg/ddp357.
38. Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase egulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012;55(3):781–789. doi: 10.1002/hep.24806.
39. Mancina RM, Dongiovanni P, Petta S, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150(5): 1219–1230. doi: 10.1053/j.gastro.2016.01.032.
40. Buch S, Stickel F, Trepo E, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015;47(12):1443–1448. doi: 10.1038/ng.3417.
41. Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1026–1037. doi: 10.1016/j.metabol.2015.08.018.
42. Gijon MA, Riekhof WR, Zarini S, et al. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. Biol Chem. 2008;283(44):30235–30245. doi: 10.1074/jbc.M806194200.
43. Serini S, Piccioni E, Merendino N, et al. Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis. 2009;14(2):135–152. doi: 10.1007/s10495-008-0298-2.
44. Luukkonen PK, Zhou Y, Hyotylainen T, et al. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J Hepatol. 2016;65(6):1263–1265. doi: 10.1016/j.jhep.2016.07.045.
45. Donati B, Dongiovanni P, Romeo S,et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7(1):4492. doi: 10.1038/s41598-017-04991-0.
46. Abul-Husn NS,Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096–1106. doi: 10.1056/NEJMoa1712191.
47. Su W, Wang Y, Jia X, et al. Comparative proteomic study reveals 17-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2014;111(31):11437–11442. doi: 10.1073/pnas.1410741111.
48. Kneeman JM, Misdraji J, Corey KE. Secondary causes of nonalcoholic fatty liver disease. Therap Adv Gastroenterol. 2012;5(3): 199–207. doi: 10.1177/1756283X11430859.
49. Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014;25(3):161–168. doi: 10.1097/MOL.0000000000000072.
50. Cefalu AB, Pirruccello JP, Noto D, et al. A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol. 2013;33(8):2021–2025. doi: 10.1161/atvbaha.112.301101.
51. Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoproteincholesterol. Am J Hum Genet. 2006;78(3):410–422. doi: 10.1086/500615.
52. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370(19):1809–1819. doi: 10.1056/NEJMoa1316222.
53. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–1499. doi: 10.1056/NEJMoa1501031.
54. Collins JC, Scheinberg IH, Giblin DR, et al. Hepatic peroxisomal abnormalities in abetalipoproteinemia. Gastroenterology. 1989; 97(3):766–770. doi: 10.1016/0016-5085(89)90651-3.
55. Sacks FM, Stanesa M, Hegele RA. Severe hypertriglyceridemia with pancreatitis: thirteen years’ treatment with lomitapide. JAMA Intern Med. 2014;174(3):443–447. doi: 10.1001/jamainternmed.2013.13309.
56. Olivieri O, Stranieri C, Bassi A, et al. ApoC-III gene polymorphisms and risk of coronary artery disease. J Lipid Res. 2002;43(9): 1450–1457. doi: 10.1194/jlr.M200145-JLR200.
57. Bell TA, Graham MJ, Baker BF, Crooke RM. Therapeutic inhibition of apoC-III for the treatment of hypertriglyceridemia. Clin Lipidol. 2015;10(2):191–203. doi: 10.2217/clp.15.7.
58. Pisciotta L, Fresa R, Bellocchio A, et al. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene. Mol Genet Metab. 2009;97(2):143–148. doi: 10.1016/j.ymgme.2009.02.007.
59. Bernstein DL, Hulkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230–1243. doi: 10.1016/j.jhep.2013.02.014.
60. Jones SA, Bernstein DL, Bialer MG, et al. Severe and rapid disease course in the natural history of infants with lysosomal acid lipase deficiency. Mol Genet Metab. 2014;111(2):57–58. doi: 10.1016/j.ymgme.2013.12.125.
61. Reiner Z, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency — an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21–30. doi: 10.1016/j.atherosclerosis.2014.04.003.
62. Hubbard B, Doege H, Punreddy S, et al. Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity. Gastroenterology. 2006;130(4):1259–1269. doi: 10.1053/j.gastro.2006.02.012.
63. Auinger A, Valenti L, Pfeuffer M, et al. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res. 2010;42(12):854–859. doi: 10.1055/s-0030-1267186.
64. Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31(3): 430–434. doi: 10.1016/S0168-8278(99)80033-6.
65. Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–1887. doi: 10.1002/hep.22848.
66. Berardi MJ, Chou JJ. Fatty acid flippase activity of UCP2 is essential for its proton transport in mitochondria. Cell Metab. 2014;20(3): 541–552. doi: 10.1016/j.cmet.2014.07.004.
67. Fares R, Petta S, Lombardi R, et al. The UCP2-866 G>A promoter region polymorphism is associated with nonalcoholic steatohepatitis. Liver Int. 2015;35(5):1574–1580. doi: 10.1111/liv.12707.
68. Al-Serri A, Anstee QM, Valenti L, et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from casecontrol and intra-familial allele association studies. J Hepatol. 2012;56(2):448–454. doi: 10.1016/j.jhep.2011.05.029.
69. Petta S, Grimaudo S, Camma C, et al. IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with nonalcoholic fatty liver disease. J Hepatol. 2012;56(6):1356–1362. doi: 10.1016/j.jhep.2012.01.007.
70. Eslam M, Hashem AM, Romero-Gomez M, et al. FibroGENE: a gene-based model for staging liver fibrosis. J Hepatol. 2016;64(2): 390–398. doi: 10.1016/j.jhep.2015.11.008.
71. Musso G, Cassader M, De Michieli F, et al. Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism. Hepatology. 2012;56(3):933–942. doi: 10.1002/hep.25739.
72. Dongiovanni P, Valenti L, Rametta R, et al. Genetic variants regulating insulin receptor signaling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut. 2010;59(2):267–273. doi: 10.1136/gut.2009.190801.
73. Ishizuka Y, Nakayama K, Ogawa A, et al. TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions. J Mol Endocrinol. 2014;52(2):145–158. doi: 10.1530/JME-13-0243.
74. Bauer RC, Sasaki M, Cohen DM, et al. Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBP. J Clin Invest. 2015;125(10):3809–3818. doi: 10.1172/JCI77095.
75. Kitamoto A, Kitamoto T, Nakamura T, et al. Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. Endocr J. 2014;61(7):683–689. doi: 10.1507/endocrj.ej14-0052.
76. Calado RT, Regal JA, Kleiner DE, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009;4(11):e7926. doi: 10.1371/journal.pone.0007926.
77. Aravinthan A, Scarpini C, Tachtatzis P, et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol. 2013;58(3):549–556. doi: 10.1016/j.jhep.2012.10.031.
78. Ratziu V, Lalazar A, Wong L, et al. Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc Natl Acad Sci U S A. 1998;95(16):9500–9505. doi: 10.1073/pnas.95.16.9500.
79. Bechmann LP, Gastaldelli A, Vetter D, et al. Glucokinase links Kruppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease. Hepatology. 2012;55(4):1083–1093. doi: 10.1002/hep.24793.
80. Miele L, Beale G, Patman G, et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135(1):282–291.e1. doi: 10.1053/j.gastro.2008.04.004.
81. Lee HJ, Choi JS, Lee HJ, et al. Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction. J Nutr Biochem. 2015;26(12):1414–1423. doi: 10.1016/j.jnutbio.2015.07.008.
82. Ruddell RG, Hoang-le D, Barwood JM, et al. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009;49(3):887–900. doi: 10.1002/hep.22716.
83. Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010;138(3):905–912. doi: 10.1053/j.gastro.2009.11.013.
Рецензия
При поддержке: Обзор литературы подготовлен в рамках реализации научной программы, поддержанной грантом Российского научного фонда (проект № 17-15-01475).
Для цитирования:
Богомолов П.О., Кокина К.Ю., Майоров А.Ю., Мишина Е.Е. Генетические аспекты неалкогольной жировой болезни печени. Вопросы современной педиатрии. 2018;17(6):442-448. https://doi.org/10.15690/vsp.v17i6.1974
For citation:
Bogomolov P.O., Kokina K.Yu., Mayorov A.Yu., Mishina E.E. Genetic Aspects of Non-Alcoholic Fatty Liver Disease. Current Pediatrics. 2018;17(6):442-448. (In Russ.) https://doi.org/10.15690/vsp.v17i6.1974
Просмотров: 24687
Послать статью по эл. почте 
