The Role of MMP-2 and MMP-9 in the Relationship of Inflammation, Fibrosis and Apoptosis During the Progression of Non-Alcoholic Fatty Liver Disease and the Diagnostic Significance of the Plasma Level of Their Active Forms

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

MMP-2 and MMP-9 play an important role in the pathogenesis of chronic liver diseases, participating in the processes of inflammation and fibrosis. Their role in the progression of non-alcoholic fatty liver disease (NAFLD) is poorly understood. The analysis of MMP-2, -9 levels in the blood plasma of patients with different forms of NAFLD (liver steatosis (LS) and non-alcoholic steatohepatitis (NASH) of weak (-WA), moderate (MA), high (-HA) activity without pronounced fibrosis) was performed. Correlations between the levels of MMP-2, -9 and mRNA of the genes MMP2, MMP9, ADAM17, NLRP3, caspase 3 activity in peripheral blood leukocytes (PBL), TNFα, IL-6, sIL-6R, cytokeratin-18 fragments in plasma were assessed. In steatosis, the levels of MMP2 gene mRNA in PBL and MMP-2 in plasma are lower than in the control, and the expression of the NLRP3 gene in PBL is increased relative to other groups. In NASH-WA, the level of MMP-9 is higher than in the control, LS, and NASH-MA, which can be associated with the activation of inflammation during the transformation of LS into NASH. The plasma level of MMP-9 over 389.50 pg/ml is diagnostically significant for the detection of NASH-WA among steatosis patients (AUC ROC = 0.818, 95% CI = 0.689–0.948, p < 0.001). In NAFLD, the level of MMP-9 can be associated not only with inflammation, but also with apoptosis. ADAM17 probably plays a certain role in this regard. In advanced NASH, hepatocyte apoptosis is increased, the level of caspase 3 activity in PBL is increased, the level of MMP-9 in the blood is reduced to the level of the control and LS. In NASH-HA, the level of mRNA of the ADAM17 gene in PBL is increased compared to the control, NASH-WA and NASH-MA. Thus, MMP-2 and MMP-9 are involved in the pathogenesis of NAFLD already at early stages and their level in the blood can be associated with the presence and activity of inflammation in the liver parenchyma.

Full Text

Restricted Access

About the authors

I. V. Kurbatova

Karelian Research Centre of the Russian Academy of Sciences

Author for correspondence.
Email: irina7m@yandex.ru
Russian Federation, 185910, Petrozavodsk, Karelia

L. V. Topchieva

Karelian Research Centre of the Russian Academy of Sciences

Email: irina7m@yandex.ru
Russian Federation, 185910, Petrozavodsk, Karelia

O. P. Dudanova

Petrozavodsk State University

Email: irina7m@yandex.ru
Russian Federation, 185910, Petrozavodsk, Karelia

A. A. Shipovskaya

Petrozavodsk State University

Email: irina7m@yandex.ru
Russian Federation, 185910, Petrozavodsk, Karelia

References

  1. Маевская М. В., Котовская Ю. В., Ивашкин В. Т., Ткачева О. Н., Трошина Е. А., Шестакова М. В., Бредер В. В., Гейвандова Н. И., Дощицин В. Л., Дудинская Е. Н., Ершова Е. В., Кодзоева Х. Б., Комшилова К. А., Корочанская Н. В., Майоров А. Ю., Мишина Е. Е., Надинская М. Ю., Никитин И. Г., Погосова Н. В., Тарзиманова А. И., Шамхалова М. Ш. (2022) Национальный Консенсус для врачей по ведению взрослых пациентов с неалкогольной жировой болезнью печени и ее основными коморбидными состояниями, Тер. Архив, 94, 216-253, https://doi.org/10.26442/00403660.2022.02.201363.
  2. Le, M. H., Yeo, Y. H., Li, X., Li, J., Zou, B., Wu, Y., Ye, Q., Huang, D. Q., Zhao, C., Zhang, J., Liu, C., Chang, N., Xing, F., Yan, S., Wan, Z. H., Tang, N. S. Y., Mayumi, M., Liu, X., Liu, C., Rui, F., Yang, H., Yang, Y., Jin, R., Le, R. H. X., Xu, Y., Le, D. M., Barnett, S., Stave, C. D., et al. (2022) 2019 global NAFLD prevalence: a systematic review and meta-analysis, Clin. Gastroenterol. Hepatol., 20, 2809-2817.e28, https://doi.org/10.1016/j.cgh.2021.12.002.
  3. Younossi, Z. M., Golabi, P., Paik, J. M., Henry, A., Van Dongen, C., and Henry, L. (2023) The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review, Hepatology, 77, 1335-1347, https://doi.org/10.1097/HEP.0000000000000004.
  4. Riazi, K., Azhari, H., Charette, J. H., Underwood, F. E., King, J. A., Afshar, E. E., Swain, M. G., Congly, S. E., Kaplan, G. G., and Shaheen, A. A. (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis, Lancet Gastroenterol. Hepatol., 7, 851-861, https://doi.org/10.1016/S2468-1253(22)00165-0.
  5. Маев И. В., Андреев Д. Н., Кучерявый Ю. А. (2023) Распространенность неалкогольной жировой болезни печени в России: мета-анализ, Consilium Medicum, 25, 313-319, https://doi.org/10.26442/20751753.2023.5.202155.
  6. Arab, J. P., Arrese, M., and Trauner, M. (2018) Recent insights into the pathogenesis of nonalcoholic fatty liver disease, Annu. Rev. Pathol., 13, 321-350, https://doi.org/10.1146/annurev-pathol-020117-043617.
  7. Parthasarathy, G., Revelo, X., and Malhi, H. (2020) Pathogenesis of nonalcoholic steatohepatitis: an overview, Hepatol. Commun., 4, 478-492, https://doi.org/10.1002/hep4.1479.
  8. Loomba, R., Friedman, S. L., and Shulman, G. I. (2021) Mechanisms and disease consequences of nonalcoholic fatty liver disease, Cell, 184, 2537-2564, https://doi.org/10.1016/j.cell.2021.04.015.
  9. Lee, K. C., Wu, P. S., and Lin, H. C. (2023) Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis, Clin. Mol. Hepatol., 29, 77-98, https://doi.org/10.3350/cmh.2022.0237.
  10. Tilg, H., and Moschen, A. R. (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis, Hepatology, 52, 1836-1846, https://doi.org/10.1002/hep.24001.
  11. Buzzetti, E., Pinzani, M., and Tsochatzis, E. A. (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD), Metabolism, 65, 1038-1048, https://doi.org/10.1016/j.metabol.2015.12.012.
  12. Ziolkowska, S., Binienda, A., Jabłkowski, M., Szemraj, J., and Czarny, P. (2021) The interplay between insulin resistance, inflammation, oxidative stress, base excision repair and metabolic syndrome in nonalcoholic fatty liver disease, Int. J. Mol. Sci., 22, 11128, https://doi.org/10.3390/ijms222011128.
  13. Lambert, J. E., Ramos-Roman, M. A., Browning, J. D., and Parks, E. J. (2014) Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease, Gastroenterology, 146, 726-735, 209, https://doi.org/10.1053/j.gastro.2013.11.049.
  14. Nassir, F. (2022) NAFLD: Mechanisms, treatments, and biomarkers, Biomolecules, 12, 824, https://doi.org/10.3390/biom12060824.
  15. Fujii, H., Kawada, N., and Japan Study Group of Nafld Jsg-Nafld (2020) The role of insulin resistance and diabetes in nonalcoholic fatty liver disease, Int. J. Mol. Sci., 21, 3863, https://doi.org/10.3390/ijms21113863.
  16. Jung, U. J., and Choi, M. S. (2014) Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease, Int. J. Mol. Sci., 15, 6184-6223, https://doi.org/10.3390/ijms15046184.
  17. Ji, Y., Yin, Y., Li, Z., and Zhang, W. (2019) Gut microbiota-derived components and metabolites in the progression of non-alcoholic fatty liver disease (NAFLD), Nutrients, 11, 1712, https://doi.org/10.3390/nu11081712.
  18. Anwar, S. D., Foster, C., and Ashraf, A. (2023) Lipid disorders and metabolic-associated fatty liver disease, Endocrinol. Metab. Clin. North Am., 52, 445-457, https://doi.org/10.1016/j.ecl.2023.01.003.
  19. Ивашкин В. Т., Маевская М. В., Жаркова М. С., Котовская Ю. В., Ткачева О. Н., Трошина Е. А., Шестакова М. В., Маев И. В., Бредер В. В., Гейвандова Н. И., Дощицин В. Л., Дудинская Е. Н., Ершова Е. В., Кодзоева Х. Б., Комшилова К. А., Корочанская Н. В., Майоров А. Ю., Мишина Е. Е., Надинская М. Ю., Никитин И. Г., Погосова Н. В., Тарзиманова А. И., Шамхалова М. Ш. (2022) Клинические рекомендации Российского общества по изучению печени, Российской гастроэнтерологической ассоциации, Российской ассоциации эндокринологов, Российской ассоциации геронтологов и гериатров и Национального общества профилактической кардиологии по диагностике и лечению неалкогольной жировой болезни печени, Росс. Журн. Гастроэнтерол. Гепатол. Колопроктол., 32, 104-140, https://doi.org/10.22416/ 1382-4376-2022-32-4-104-140.
  20. Powell, E. E., Wong, V. W., and Rinella, M. (2021) Non-alcoholic fatty liver disease, Lancet, 397, 2212-2224, https://doi.org/10.1016/S0140-6736(20)32511-3.
  21. Angulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., Haflidadottir, S., and Bendtsen, F. (2015) Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease, Gastroenterology, 149, 389-397.e10, https://doi.org/10.1053/j.gastro.2015.04.043.
  22. Ratziu, V., Charlotte, F., Heurtier, A., Gombert, S., Giral, P., Bruckert, E., Grimaldi, A., Capron, F., and Poynard, T., and LIDO Study Group. (2005) Sampling variability of liver biopsy in nonalcoholic fatty liver disease, Gastroenterology, 128, 1898-1906, https://doi.org/10.1053/j.gastro.2005.03.084.
  23. Portincasa, P. (2023) NAFLD, MAFLD, and beyond: one or several acronyms for better comprehension and patient care, Intern. Emerg. Med., 18, 993-1006, https://doi.org/10.1007/s11739-023-03203-0.
  24. Iqbal, U., Perumpail, B. J., Akhtar, D., Kim, D., and Ahmed, A. (2019) The epidemiology, risk profiling and diagnostic challenges of nonalcoholic fatty liver disease, Medicines (Basel), 6, 41, https://doi.org/10.3390/ medicines6010041.
  25. García-Compeán, D., and Jiménez-Rodríguez, A. R. (2022) NAFLD VS MAFLD. The evidence-based debate has come. Time to change? Ann. Hepatol., 27, 100765, https://doi.org/10.1016/j.aohep.2022.100765.
  26. Kaya, E., and Yilmaz, Y. (2022) Metabolic-associated fatty liver disease (MAFLD): a multi-systemic disease beyond the liver, J. Clin. Transl. Hepatol., 10, 329-338, https://doi.org/10.14218/JCTH.2021.00178.
  27. Parola, M., and Pinzani, M. (2019) Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues, Mol. Aspects Med., 65, 37-55, https://doi.org/10.1016/j.mam.2018.09.002.
  28. Böttcher, K., and Pinzani, M. (2017) Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents, Adv. Drug Deliv. Rev., 121, 3-8, https://doi.org/10.1016/j.addr.2017.05.016.
  29. Geervliet, E., and Bansal, R. (2020) Matrix metalloproteinases as potential biomarkers and therapeutic targets in liver diseases, Cells, 9, 1212, https://doi.org/10.3390/cells9051212.
  30. Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., Iwaisako, K., Moore-Morris, T., Scott, B., Tsukamoto, H., Evans, S. M., Dillmann, W., Glass, C. K., and Brenner, D. A. (2012) Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis, Proc. Natl. Acad. Sci. USA, 109, 9448-9453, https://doi.org/ 10.1073/pnas.1201840109.
  31. Roehlen, N., Crouchet, E., and Baumert, T. F. (2020) Liver fibrosis: mechanistic concepts and therapeutic perspectives, Cells, 9, 875, https://doi.org/10.3390/cells9040875.
  32. Zhao, Y. Q., Deng, X. W., Xu, G. Q., Lin, J., Lu, H. Z., and Chen, J. (2023) Mechanical homeostasis imbalance in hepatic stellate cells activation and hepatic fibrosis, Front. Mol. Biosci., 10, 1183808, https://doi.org/10.3389/fmolb.2023.1183808.
  33. Ortiz, C., Schierwagen, R., Schaefer, L., Klein, S., Trepat, X., and Trebicka, J. (2021) Extracellular matrix remodeling in chronic liver disease, Curr. Tissue Microenviron. Rep., 2, 41-52, https://doi.org/10.1007/s43152-021-00030-3.
  34. Giannandrea, M., and Parks, W. C. (2014) Diverse functions of matrix metalloproteinases during fibrosis, Dis. Model Mech., 7, 193-203, https://doi.org/10.1242/dmm.012062.
  35. Iredale, J. P., Thompson, A., and Henderson, N. C. (2013) Extracellular matrix degradation in liver fibrosis: biochemistry and regulation, Biochim. Biophys. Acta, 7, 876-883, https://doi.org/10.1016/j.bbadis.2012.11.002.
  36. Roeb, E. (2018) Matrix metalloproteinases and liver fibrosis (translational aspects), Matrix Biol., 68-69, 463-473, https://doi.org/10.1016/j.matbio.2017.12.012.
  37. Alshanwani, A. R., Hagar, H., Shaheen, S., Alhusaini, A. M., Arafah, M. M., Faddah, L. M., Alharbi, F. M., Sharma A. K., Fayed, A., and Badr, A. M. (2022) A promising antifibrotic drug, pyridoxamine attenuates thioacetamide-induced liver fibrosis by combating oxidative stress, advanced glycation end products, and balancing matrix metalloproteinases, Eur. J. Pharmacol., 923, 174910, https://doi.org/10.1016/j.ejphar.2022.174910.
  38. Shan, L., Wang, F., Zhai, D., Meng, X., Liu, J., and Lv, X. (2023) Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis, Biomed. Pharmacother., 161, 114472, https://doi.org/10.1016/j.biopha.2023.114472.
  39. Radbill, B. D., Gupta, R., Ramirez, M. C. M., DiFeo, A., Martignetti, J. A., Alvarez, C. E., Friedman, S. L., Narla, G., Vrabie, R., Bowles, R., Saiman, Y., and Bansal, M. B. (2011) Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression, Dig. Dis. Sci., 56, 406-416, https:// doi.org/10.1007/s10620-010-1296-0.
  40. Onozuka, I., Kakinuma, S., Kamiya, A., Miyoshi, M., Sakamoto, N., Kiyohashi, K., Watanabe, T., Funaoka, Y., Ueyama, M., Nakagawa, M., Koshikawa, N., Seiki, M., Nakauchi, H., and Watanabe, M. (2011) Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice, Biochem. Biophys. Res. Commun., 406, 134-140, https://doi.org/10.1016/j.bbrc.2011.02.012.
  41. Zhou, X., Murphy, F. R., Gehdu, N., Zhang, J., Iredale, J. P., and Benyon, R. C. (2004) Engagement of αvβ3 integrin regulates proliferation and apoptosis of hepatic stellate cells, J. Biol. Chem., 279, 23996-24006, https://doi.org/10.1074/jbc.M311668200.
  42. Melgar-Lesmes, P., Luquero, A., Parra-Robert, M., Mora, A., Ribera, J., Edelman, E. R., and Jiménez, W. (2018) Graphene-dendrimer nanostars for targeted macrophage overexpression of metalloproteinase 9 and hepatic fibrosis precision therapy, Nano Lett., 18, 5839-5845, https://doi.org/10.1021/acs.nanolett.8b02498.
  43. Feng, M., Ding, J., Wang, M., Zhang, J., Zhu, X., and Guan, W. (2018) Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution, Int. J. Biol. Sci., 14, 1033-1040, https://doi.org/10.7150/ijbs.25589.
  44. Wang, Q., Liu, X., Zhang, J., Lu, L., Feng, M., and Wang, J. (2019) Dynamic features of liver fibrogenesis and fibrosis resolution in the absence of matrix metalloproteinase 9, Mol. Med. Rep., 20, 5239-5248, https:// doi.org/10.3892/mmr.2019.10740.
  45. Kurzepa, J., Mądro, A., Czechowska, G., Kurzepa, J., Celiński, K., Kazmierak, W., and Slomka, M. (2014) Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases, Hepatobiliary Pancreat. Dis. Int., 13, 570-579, https://doi.org/10.1016/s14993872(14)60261-7.
  46. Flannery, C. R. (2006) MMPs and ADAMTSs: functional studies, Front. Biosci., 11, 544-569, https://doi.org/ 10.2741/1818.
  47. Le, N. T., Xue, M., Castelnoble, L. A., and Jackson, C. J. (2007) The dual personalities of matrix metalloproteinases in inflammation, Front. Biosci., 12, 1475-1487, https://doi.org/10.2741/2161.
  48. Kato, H., Kuriyama, N., Duarte, S., Clavien, P. A., Busuttil, R. W, and Coito, A. J. (2014) MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury, J. Hepatol., 60, 1032-1039, https://doi.org/10.1016/j.jhep.2013.12.022.
  49. Hamada, T., Duarte, S., Tsuchihashi, S., Busuttil, R. W., and Coito, A. J. (2009) Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury, Am. J. Pathol., 174, 2265-2277, https://doi.org/10.2353/ajpath.2009.080872.
  50. Fernandez-Patron, C., Zouki, C., Whittal, R., Chan, J. S., Davidge, S. T., and Filep, J. G. (2001) Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin-1[1-32], FASEB J., 15, 2230-2240, https://doi.org/10.1096/fj.01-0178com.
  51. Gearing, A. J., Beckett, P., Christodoulou, M., Churchill, M., Clements, J., Davidson, A. H., Drummond, A. H., Galloway, W. A., Gilbert, R., Gordon, J. L., et al. (1994) Processing of tumour necrosis factor-alpha precursor by metalloproteinases, Nature, 370, 555-557, https://doi.org/10.1038/370555a0.
  52. Fernandez-Patron, C., Kassiri, Z., and Leung, D. (2016) Modulation of systemic metabolism by MMP-2: from MMP-2 deficiency in mice to MMP-2 deficiency in patients, Compr. Physiol., 6, 1935-1949, https://doi.org/10.1002/cphy.c160010.
  53. McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C.A., Clark-Lewis, I., and Overall, C. M. (2000) Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3, Science, 289, 1202-1206, https:// doi.org/10.1126/science.289.5482.1202.
  54. Ito, A., Mukaiyama, A., Itoh, Y., Nagase, H., Thogersen, I. B., Enghild, J. J., Sasaguri, Y., and Mori, Y. (1996) Degradation of interleukin 1beta by matrix metalloproteinases, J. Biol. Chem., 271, 14657-14660, https://doi.org/10.1074/jbc.271.25.14657.
  55. Calabro, S. R., Maczurek, A. E., Morgan, A. J., Tu, T., Wen, V. W., Yee, C., Mridha, A., Lee, M., d’Avigdor, W., Locarnini, S. A., McCaughan, G. W., Warner, F. J., McLennan, S. V., and Shackel, N. A. (2014) Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis, PLoS One, 9, e90571, https:// doi.org/10.1371/journal.pone.0090571.
  56. Xue, M., March, L., Sambrook, P. N., and Jackson, C. J. (2007) Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis, Arthritis Rheum., 56, 2864-2874, https://doi.org/10.1002/art.22844.
  57. Lichtinghagen, R., Bahr, M. J., Wehmeier, M., Michels, D., Haberkorn, C. I., Arndt, B., Flemming, P., Manns, M. P., and Boeker, K. H. (2003) Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis, Clin. Sci. (Lond), 105, 373-382, https://doi.org/10.1042/CS20030098.
  58. Takahara, T., Furui, K., Yata, Y., Jin, B., Zhang, L. P., Nambu, S., Sato, H., Seiki, M., and Watanabe, A. (1997) Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers, Hepatology, 26, 1521-1529, https://doi.org/10.1002/hep.510260620.
  59. Prystupa, A., Boguszewska-Czubara, A., Bojarska-Junak, A., Toruń-Jurkowska, A., Roliński, J., and Załuska, W. (2015) Activity of MMP-2, MMP-8 and MMP-9 in serum as a marker of progression of alcoholic liver disease in people from Lublin Region, eastern Poland, Ann. Agric. Environ. Med., 22, 325-328, https://doi.org/ 10.5604/12321966.1152088.
  60. Cursio, R., Mari, B., Louis, K., Rostagno, P., Saint-Paul, M. C., Giudicelli, J., Bottero, V., Anglard, P., Yiotakis, A., Dive, V., Gugenheim, J., and Auberger, P. (2002) Rat liver injury after normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor, FASEB J., 16, 93-95, https://doi.org/10.1096/fj.01-0279fje.
  61. Giannelli, G., Bergamini, C., Marinosci, F., Fransvea, E., Quaranta, M., Lupo, L., Schiraldi, O., and Antonaci, S. (2002) Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma, Int. J. Cancer., 97, 425-431, https://doi.org/10.1002/ijc.1635.
  62. Benyon, R. C., Hovell, C. J., Da Gaça, M., Jones, E. H., Iredale, J. P., and Arthur, M. J. (1999) Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation, Hepatology, 30, 977-986, https://doi.org/10.1002/hep.510300431.
  63. Kim, W. U., Min, S. Y., Cho, M. L., Hong, K. H., Shin, Y. J., Park, S. H., and Cho, C. S. (2005) Elevated matrix metalloproteinase-9 in patients with systemic sclerosis, Arthritis Res. Ther., 7, R71-R79, https://doi.org/10.1186/ar1454.
  64. Zhao, Y., Yakufu, M., Ma, C., Wang, B., Yang, J., and Hu, J. (2024) Transcriptomics reveal a molecular signature in the progression of nonalcoholic steatohepatitis and identifies PAI 1 and MMP 9 as biomarkers in in vivo and in vitro studies, Mol. Med. Rep., 29, 15, https://doi.org/10.3892/mmr.2023.13138.
  65. Sun, M. H., Han, X. C., Jia, M. K., Jiang, W. D., Wang, M., Zhang, H., Han, G., and Jiang, Y. (2005) Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma, World J. Gastroenterol., 11, 5931-5937, https://doi.org/10.3748/wjg.v11.i38.5931.
  66. Murthy, S., Ryan, A., He, C., Mallampalli, R. K., and Carter, A. B. (2010) Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1, J. Biol. Chem., 285, 25062-25073, https://doi.org/10.1074/jbc.M109.099655.
  67. Olle, E. W., Ren, X., McClintock, S. D., Warner, R. L., Deogracias, M. P., Johnson, K. J., and Colletti, L. M. (2006) Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice, Hepatology, 44, 540-549, https://doi.org/10.1002/hep.21314.
  68. Yu, Q., and Stamenkovic, I. (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis, Genes Dev., 14, 163-176.
  69. Kaviratne, M., Hesse, M., Leusink, M., Cheever, A. W., Davies, S. J., McKerrow, J. H., Wakefield, L. M., Letterio, J. J., and Wynn, T. A. (2004) IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent, J. Immunol., 173, 4020-4029, https://doi.org/10.4049/jimmunol.173.6.4020.
  70. Schönbeck, U., Mach, F., and Libby, P. (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing, J. Immunol., 161, 3340-3346.
  71. Trojanek, J. B., Michałkiewicz, J., Grzywa-Czuba, R., Jańczyk, W., Gackowska, L., Kubiszewska, I., Helmin-Basa, A., Wierzbicka-Rucińska, A., Szalecki, M., and Socha, P. (2020) Expression of matrix metalloproteinases and their tissue inhibitors in peripheral blood leukocytes and plasma of children with nonalcoholic fatty liver disease, Mediators Inflamm., 2020, 8327945, https://doi.org/10.1155/2020/8327945.
  72. Kupčová, V., Fedelešová, M., Bulas, J., Kozmonová, P., and Turecký, L. (2019) Overview of the pathogenesis, genetic, and non-invasive clinical, biochemical, and scoring methods in the assessment of NAFLD, Int. J. Environ. Res. Public Health, 16, 3570, https://doi.org/10.3390/ijerph16193570.
  73. Ливзан М. А., Ахмедов В. А., Кролевец Т. С., Гаус О. В., Черкащенко Н. А. (2016) Информативность неинвазивных маркеров фиброза печени у пациентов с неалкогольной жировой болезнью печени, Тер. Архив, 88, 62-68, https://doi.org/10.17116/terarkh2016881262-68.
  74. Kumar, S., Duan, Q., Wu, R., Harris, E. N., and Su, Q. (2021) Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis, Adv. Drug Deliv. Rev., 176, 113869, https://doi.org/10.1016/j.addr.2021.113869.
  75. Afonso, M. B., Castro, R. E., and Rodrigues, C. M. P. (2019) Processes exacerbating apoptosis in non-alcoholic steatohepatitis, Clin. Sci. (Lond), 133, 2245-2264, https://doi.org/10.1042/CS20190068.
  76. Peiseler, M., Schwabe, R., Hampe, J., Kubes, P., Heikenwälder, M., and Tacke, F. (2022) Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits, J. Hepatol., 77, 1136-1160, https://doi.org/10.1016/j.jhep.2022.06.012.
  77. Курбатова И. В., Дуданова О. П. (2017) Особенности некротически-воспалительного процесса при разных формах неалкогольной жировой болезни печени, Тер. Архив, 89, 52-58, https://doi.org/10.17116/terarkh201789252-58.
  78. Курбатова И. В., Топчиева Л. В., Дуданова О. П., Шиповская А. А. (2022) Роль растворимого рецептора интерлейкина-6 в прогрессировании НАЖБП, Бюлл. Эксп. Биол. Мед., 174, 585-591, https://doi.org/10.47056/ 0365-9615-2022-174-11-585-591.
  79. Li, Y. Q., Yan, J. P., Xu, W. L., Wang, H., Xia, Y. J., Wang, H. J., Zhu, Y. Y., and Huang, X. J. (2013) ADAM17 mediates MMP9 expression in lung epithelial cells, PLoS One, 8, e51701, https://doi.org/10.1371/journal. pone.0051701.
  80. Schmidt-Arras, D., and Rose-John, S. (2019) Regulation of fibrotic processes in the liver by ADAM proteases, Cells, 8, 1226, https://doi.org/10.3390/cells8101226.
  81. Wree, A., McGeough, M. D., Peña, C. A., Schlattjan, M., Li, H., Inzaugarat, M. E., Messer, K., Canbay, A., Hoffman, H. M., and Feldstein, A. E. (2014) NLRP3 inflammasome activation is required for fibrosis development in NAFLD, J. Mol. Med. (Berl), 92, 1069-1082, https://doi.org/10.1007/s00109-014-1170-1.
  82. Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A., and Bacon, B. R. (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions, Am. J. Gastroenterol., 94, 2467-2474, https://doi.org/10.1111/j.1572-0241.1999.01377.x.
  83. Friedewald, W. T., Levy, R. I., and Fredrickson, D. S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge, Clin. Chem., 18, 499-502.
  84. Sterling, R. K., Lissen, E., Clumeck, N., Sola, R., Correa, M. C., Montaner, J., S. Sulkowski, M., Torriani, F. J., Dieterich, D. T., Thomas, D. L., Messinger, D., and Nelson, M., and APRICOT Clinical Investigators (2006) Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection, Hepatology, 43, 1317-1325, https://doi.org/10.1002/hep.21178.
  85. Shah, A. G., Lydecker, A., Murray, K., Tetri, B. N., Contos, M. J., and Sanyal, A. J., and Nash Clinical Research Network (2009) Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease, Clin. Gastroenterol. Hepatol., 7, 1104-1112, https://doi.org/10.1016/j.cgh.2009.05.033.
  86. Wai, C. T., Greenson, J. K., Fontana, R. J., Kalbfleisch, J. D., Marrero, J. A., Conjeevaram, H. S., and Lok, A. S. (2003) A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C, Hepatology, 38, 518-526, https://doi.org/10.1053/jhep.2003.50346.
  87. Loaeza-del-Castillo, A., Paz-Pineda, F., Oviedo-Cárdenas, E., Sánchez-Avila, F., and Vargas-Vorácková, F. (2008) AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis, Ann. Hepatol., 7, 350-357.
  88. Драпкина О. М., Шепель Р. Н., Яковенко Э. П., Зятенкова Е. В. (2019) Неинвазивные методы выявления прогрессирующего фиброза у пациентов с неалкогольной жировой болезнью печени, Профилакт. Мед., 22, 82-88, https://doi.org/10.17116/profmed20192202182.
  89. ACK Lysis Buffer (2014) Cold Spring Harb. Protoc., https://doi.org/10.1101/pdb.rec083295.
  90. Livak, K. J., and Schmittgen, T. D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–∆∆CT method, Methods, 25, 402-408, https://doi.org/10.1006/meth.2001.1262.
  91. Youden, W. J. (1950) Index for rating diagnostic tests, Cancer, 3, 32-35, https://doi.org/10.1002/10970142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3.
  92. Zweig, M. H., and Campbell, G. (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine, Clin. Chem., 39, 561-577.
  93. Ren, J. J., Huang, T. J., Zhang, Q. Q., Zhang, H. Y., Guo, X. H., Fan, H. Q., Li, R. K., and Liu, L. X. (2019) Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice, Hepatobiliary Pancreat. Dis. Int., 18, 38-47, https://doi.org/10.1016/j.hbpd.2018.08.008.
  94. Tarantino, G., Savastano, S., and Colao, A. (2010) Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance, World J. Gastroenterol., 16, 4773-4783, https://doi.org/10.3748/ wjg.v16.i38.4773.
  95. Yu, H., Lin, L., Zhang, Z., Zhang, H., and Hu, H. (2020) Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study, Signal Transduct. Target Ther., 5, https://doi.org/10.1038/s41392-020-00312-6.
  96. Kawai, T., Autieri, M. V., and Scalia, R. (2021) Adipose tissue inflammation and metabolic dysfunction in obesity, Am. J. Physiol. Cell Physiol., 320, 375-391, https://doi.org/10.1152/ajpcell.00379.2020.
  97. Li, H., Meng, Y., He, S., Tan, X., Zhang, Y., Zhang, X., Wang, L., and Zheng, W. (2022) Macrophages, chronic inflammation, and insulin resistance, Cells, 11, https://doi.org/10.3390/cells11193001.
  98. De Carvalho Ribeiro, M., and Szabo, G. (2022) Role of the inflammasome in liver disease, Annu. Rev. Pathol., 17, 345-365, https://doi.org/10.1146/annurev-pathmechdis-032521-102529.
  99. Csak, T., Ganz, M., Pespisa, J., Kodys, K., Dolganiuc, A., and Szabo, G. (2011) Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells, Hepatology, 54, 133-144, https://doi.org/10.1002/hep.24341.
  100. Yilmaz, Y., and Eren F. (2019) Serum biomarkers of fibrosis and extracellular matrix remodeling in patients with nonalcoholic fatty liver disease: association with liver histology, Eur. J. Gastroenterol. Hepatol., 31, 43-46, https://doi.org/10.1097/MEG.0000000000001240.
  101. Wagner, J., Kumar, Y., Lautenbach, A., von Kroge, P., Wolter, S., Mann, O., Izbicki, J., Gagliani, N., and Duprée, A. (2023) Fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) as predictive values for nonalcoholic steatohepatitis (NASH), Lipids Health Dis., 22, 1, https://doi.org/10.1186/s12944-022-01764-1.
  102. Goyale, A., Jain, A., Smith, C., Papatheodoridi, M., Misas, M. G., Roccarina, D., Prat, L. I., Mikhailidis, D. P., Nair, D., and Tsochatzis, E. (2021) Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study, PLoS One, 16, e0260313, https://doi.org/10.1371/journal. pone.0260313.
  103. Scheller, J., Chalaris, A., Garbers, C., and Rose-John, S. (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration, Trends Immunol., 32, 380-387, https://doi.org/10.1016/j.it.2011.05.005.
  104. An, Y., Zhao, J., Zhang, Y., Wu, W., Hu, J., Hao, H., Qiao, Y., Tao, Y., and An, L. (2021) Rosmarinic acid induces proliferation suppression of hepatoma cells associated with NF-κB signaling pathway, Asian Pac. J. Cancer Prev., 22, 1623-1632, https://doi.org/10.31557/APJCP.2021.22.5.1623.
  105. Munsterman, I. D., Kendall, T. J., Khelil, N., Popa, M., Lomme, R., Drenth, J. P. H., and Tjwa, E. T. T. L. (2018) Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease, Histopathology, 73, 612-621, https://doi.org/10.1111/his.13665.
  106. Barchuk, M., Schreier, L., Berg, G., and Miksztowicz, V. (2018) Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis, Horm. Mol. Biol. Clin. Invest., 41, https://doi.org/10.1515/ hmbci-2018-0037.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. MMP-2 concentration in the plasma of patients with NAFLD and controls. Data are presented as: Q1-Q3, median, minimum, maximum. The p values according to the Mann-Whitney U-criterion with Bonferroni correction are indicated

Download (66KB)
Indexing metadata
3. Fig. 2. MMP-9 concentration in the plasma of patients with NAFLD and controls. Data are presented as: Q1-Q3, median, minimum, maximum. The p values according to the Mann-Whitney U-criterion with Bonferroni correction are indicated

Download (80KB)
Indexing metadata
4. Fig. 3. ROC curve for plasma MMP-9 concentration of MMP-9 in NASH-SA patients relative to SP patients. AUC = 0.818 (95% confidence interval 0.689-0.948); p < 0.001

Download (76KB)
Indexing metadata
5. Fig. 4. Schematic showing the putative relationship between changes in MMP-2 and -9 levels and different stages of NAFLD. Explanations in the text; ↑ - increase; ↓ - decrease

Download (194KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences