Пептид на основе VDAC1: перспективы использования в лечении патологий печени и поджелудочной железы

Болезни, связанные с поражением таких жизненно важных органов пищеварительной системы, как печень и поджелудочная железа, являются актуальной проблемой всемирного здравоохранения. Неалкогольная жировая болезнь печени (НАЖБП) представляет собой эпидемию мирового масштаба, проблема сахарного диабета 2-го типа (СД2) с каждым годом становится острее, гепатоцеллюлярная карцинома (ГЦК) является третьей по частоте причиной смерти от злокачественных новообразований во всем мире. Несмотря на прогресс в идентификации факторов риска, на данный момент не существует общепринятой стратегии полного излечения от названных патологий. Митохондрии, выполняя многочисленные функции, являются ключевыми органеллами клетки. VDAC1 – канал в наружной мембране митохондрий – участвует в регуляции энергетического гомеостаза клетки, клеточного стресса, концентрации ионов Ca²⁺ и играет важнейшую роль в митохондриально-опосредованном апоптозе, а также взаимодействует более чем с сотней белков. Многочисленные функции канала делают пептиды, содержащие последовательность VDAC1, привлекательными с точки зрения их использования для терапии. В данной статье рассматривается пептид на основе VDAC1 (R-Tf-D-LP4) как перспективный метод лечения метаболических нарушений, приводятся возможные механизмы, через которые пептид влияет на метаболизм жиров и углеводов. R-Tf-D-LP4 способен восстанавливать нормальную морфологию печени, уменьшая проявления жировой дистрофии гепатоцитов, явления воспаления и фиброза, замедлять рост ГЦК путем индукции апоптоза и приводить уровень глюкозы в крови близко к нормальному благодаря восстановлению нормальной морфологической структуры поджелудочной железы.

1. Neuschwander-Tetri B.A. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45. https://doi.org/10.1186/s12916-017-0806-8.

2. Law K., Brunt E.M. Nonalcoholic fatty liver disease. Clin Liver Dis. 2010;14(4):591–604. https://doi.org/10.1016/j.cld.2010.07.006.

3. Lomonaco R., Sunny N.E., Bril F., Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs. 2013;73(1):1–14. https://doi.org/10.1007/s40265-012-0004-0.

4. Zhang E., Mohammed Al-Amily I., Mohammed S., Luan C., Asplund O., Ahmed M. et al. Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells. Cell Metab. 2019;29(1):64–77.e6. https://doi.org/10.1016/j.cmet.2018.09.008.

5. Pessayre D. Role of mitochondria in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2007;22(1 Suppl.):S20–27. https://doi.org/10.1111/j.1440-1746.2006.04640.x.

6. Wallace D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751.

7. Reina S., De Pinto V. Anti-Cancer Compounds Targeted to VDAC: Potential and Perspectives. Curr Med Chem. 2017;24(40):4447–4469. https://doi.org/10.2174/0929867324666170530074039.

8. Shoshan-Barmatz V., Krelin Y., Chen Q. VDAC1 as a Player in MitochondriaMediated Apoptosis and Target for Modulating Apoptosis. Curr Med Chem. 2017;24(40):4435–4446. https://doi.org/10.2174/0929867324666170616105200.

9. Fang D., Maldonado E.N. VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation. Adv Cancer Res. 2018;138:41–69. https://doi.org/10.1016/bs.acr.2018.02.002.

10. Karachitos A., Jordan J., Kmita H. VDAC-Targeted Drugs Affecting Cytoprotection and Mitochondrial Physiology in Cerebrovascular and Cardiovascular Diseases. Curr Med Chem. 2017;24(40):4419–4434. https://doi.org/10.2174/0929867324666170530073238.

11. Shoshan-Barmatz V., Ben-Hail D., Admoni L., Krelin Y., Tripathi S.S. The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim Biophys Acta. 2015;1848(10 Pt B):2547–2575. https://doi.org/10.1016/j.bbamem.2014.10.040.

12. Prezma T., Shteinfer A., Admoni L., Raviv Z., Sela I., Levi I., Shoshan-Barmatz V. VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia. Cell Death Dis. 2013;4(9):e809. https://doi.org/10.1038/cddis.2013.316.

13. Anderson E.R., Shah Y.M. Iron homeostasis in the liver. Compr Physiol. 2013;3(1):315–330. https://doi.org/10.1002/cphy.c120016.

14. Daniels T.R., Bernabeu E., Rodríguez J.A., Patel S., Kozman M., Chiappetta D.A. et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta. 2012;1820(3):291–317. https://doi.org/10.1016/j.bbagen.2011.07.016.

15. Shteinfer-Kuzmine A., Amsalem Z., Arif T., Zooravlov A., Shoshan-Barmatz V. Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy. Mol Oncol. 2018;12(7):1077–1103. https://doi.org/10.1002/1878-0261.12313.

16. Lee K., Kerner J., Hoppel C.L. Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex. J Biol Chem. 2011;286(29):25655–15662. https://doi.org/10.1074/jbc.M111.228692.

17. Tonazzi A., Giangregorio N., Console L., Indiveri C. Mitochondrial carnitine/ acylcarnitine translocase: insights in structure/ function relationships. Basis for drug therapy and side effects prediction. Mini Rev Med Chem. 2015;15(5):396–405. https://doi.org/10.2174/138955751505150408142032.

18. Martel C., Allouche M., Esposti D.D., Fanelli E., Boursier C., Henry C. et al. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology. 2013;57(1):93–102. https://doi.org/10.1002/hep.25967.

19. Friedman S.L. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7(8):425–436. https://doi.org/10.1038/nrgastro.2010.97.

20. Pittala S., Krelin Y., Kuperman Y., Shoshan-Barmatz V. A Mitochondrial VDAC1-Based Peptide Greatly Suppresses Steatosis and NASH-Associated Pathologies in a Mouse Model. Mol Ther. 2019;27(10):1848–1862. https://doi.org/10.1016/j.ymthe.2019.06.017.

21. Feldmann H.M., Golozoubova V., Cannon B., Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9(2):203–209. https://doi.org/10.1016/j.cmet.2008.12.014.

22. Brocker C.N., Patel D.P., Velenosi T.J., Kim D., Yan T., Yue J. et al. Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice. J Lipid Res. 2018;59(11):2140–2152. https://doi.org/10.1194/jlr.M088419.

23. Pittala S., Krelin Y., Kuperman Y., Shoshan-Barmatz V. A Mitochondrial VDAC1-Based Peptide Greatly Suppresses Steatosis and NASH-Associated Pathologies in a Mouse Model. Mol Ther. 2019;27(10):1848–1862. https://doi.org/10.1016/j.ymthe.2019.06.017.

24. Ponugoti B., Kim D.H., Xiao Z., Smith Z., Miao J., Zang M. et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem. 2010;285(44):33959–33970. https://doi.org/10.1074/jbc.M110.122978.

25. Hou X., Xu S., Maitland-Toolan K.A., Sato K., Jiang B., Ido Y. et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 2008;283(29):20015–20026. https://doi.org/10.1074/jbc.M802187200.

26. Sanli T., Steinberg G.R., Singh G., Tsakiridis T. AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther. 2014;15(2):156–169. https://doi.org/10.4161/cbt.26726.

27. Fullerton M.D., Galic S., Marcinko K., Sikkema S., Pulinilkunnil T., Chen Z.P. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19(12):1649–1654. https://doi.org/10.1038/nm.3372.

28. Morris E.M., Meers G.M., Booth F.W., Fritsche K.L., Hardin C.D., Thyfault J.P., Ibdah J.A. PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion. Am J Physiol Gastrointest Liver Physiol. 2012;303(8):G979–992. https://doi.org/10.1152/ajpgi.00169.2012.

29. Grasso D., Zampieri L.X., Capelôa T., Van de Velde J.A., Sonveaux P. Mitochondria in cancer. Cell Stress. 2020;4(6):114–146. https://doi.org/10.15698/cst2020.06.221.

30. Zong W.X., Rabinowitz J.D., White E. Mitochondria and Cancer. Mol Cell. 2016;61(5):667–676. https://doi.org/10.1016/j.molcel.2016.02.011.

31. Shoshan-Barmatz V., Mizrachi D. VDAC1: from structure to cancer therapy. Front Oncol. 2012;2:164. https://doi.org/10.3389/fonc.2012.00164.

32. Arbel N., Shoshan-Barmatz V. Voltage-dependent anion channel 1-based peptides interact with Bcl-2 to prevent antiapoptotic activity. J Biol Chem. 2010;285(9):6053–6062. https://doi.org/10.1074/jbc.M109.082990.

33. Arzoine L., Zilberberg N., Ben-Romano R., Shoshan-Barmatz V. Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity. J Biol Chem. 2009;284(6):3946–3955. https://doi.org/10.1074/jbc.M803614200.

34. Abu-Hamad S., Zaid H., Israelson A., Nahon E., Shoshan-Barmatz V. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem. 2008;283(19):13482–13490. https://doi.org/10.1074/jbc.M708216200.

35. Zaid H., Abu-Hamad S., Israelson A., Nathan I., Shoshan-Barmatz V. The voltage-dependent anion channel-1 modulates apoptotic cell death. Cell Death Differ. 2005;12(7):751–760. https://doi.org/10.1038/sj.cdd.4401599.

36. Lincet H., Icard P. How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene. 2015;34(29):3751–3759. https://doi.org/10.1038/onc.2014.320.

37. Kontos C.K., Christodoulou M.I., Scorilas A. Apoptosis-related BCL2-family members: Key players in chemotherapy. Anticancer Agents Med Chem. 2014;14(3):353–374. https://doi.org/10.2174/18715206113139990091.

38. Shteinfer-Kuzmine A., Arif T., Krelin Y., Tripathi S.S., Paul A., Shoshan-Barmatz V. Mitochondrial VDAC1-based peptides: Attacking oncogenic properties in glioblastoma. Oncotarget. 2017;8(19):31329–31346. https://doi.org/10.18632/oncotarget.15455.

39. Pittala S., Krelin Y., Shoshan-Barmatz V. Targeting Liver Cancer and Associated Pathologies in Mice with a Mitochondrial VDAC1-Based Peptide. Neoplasia. 2018;20(6):594–609. https://doi.org/10.1016/j.neo.2018.02.012.

40. Shakeri R., Kheirollahi A., Davoodi J. Apaf-1: Regulation and function in cell death. Biochimie. 2017;135:111–125. https://doi.org/10.1016/j.bio-chi.2017.02.001.

41. Adams L.A., Waters O.R., Knuiman M.W., Elliott R.R., Olynyk J.K. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104(4):861–867. https://doi.org/10.1038/ajg.2009.67.

42. Pittala S., Levy I., De S., Kumar Pandey S., Melnikov N., Hyman T., Shoshan-Barmatz V. The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus. Cells. 2020;9(2):481. https://doi.org/10.3390/cells9020481.

43. Romer A.I., Sussel L. Pancreatic islet cell development and regeneration. Curr Opin Endocrinol Diabetes Obes. 2015;22(4):255–264. https://doi.org/10.1097/MED.0000000000000174.

44. Kim S.K., Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev. 2001;15(2):111–127. https://doi.org/10.1101/gad.859401.

45. Jonsson J., Carlsson L., Edlund T., Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371(6498):606–609. https://doi.org/10.1038/371606a0.

46. Kim-Muller J.Y., Kim Y.J., Fan J., Zhao S., Banks A.S., Prentki M., Accili D. FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem. 2016;291(19):10162–10172. https://doi.org/10.1074/jbc.M115.705608.