https://doi.org/10.4081/ejh.2022.3391

Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Vol. 66 No. 3 (2022)
Submitted: 1 February 2022
Accepted: 24 May 2022
Published: 21 June 2022
NAFLD/NASH, senescence, ferroptosis, beta-galactosidase, gpx4
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Authors

Antonella Vetuschi
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy.
Alfredo Cappariello
alfredo.cappariello@guest.univaq.it
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy.
Paolo Onori
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy.
Eugenio Gaudio
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy.
Giovanni Latella
Department of Life, Health and Environmental Sciences, Gastroenterology, Hepatology and Nutrition Division, University of L’Aquila, Italy.
Simona Pompili
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy.
Roberta Sferra
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy.

Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of “Western-style” diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness.

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Crossref
Scopus
Google Scholar
Europe PMC
Aravinthan AD, Alexander GJM. Senescence in chronic liver disease: Is the future in aging? J Hepatol 2016;65:825–34. DOI: https://doi.org/10.1016/j.jhep.2016.05.030
Papatheodoridi AM, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The role of senescence in the development of nonalcoholic fatty liver disease and progression to nonalcoholic steatohepatitis. Hepatology 2020;71:363-74. DOI: https://doi.org/10.1002/hep.30834
Campisi J. Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell 2005;120:513-22. DOI: https://doi.org/10.1016/j.cell.2005.02.003
Hampel B, Wagner M, Teis D, Zwerschke W, Huber LA, Jansen-Dürr P. Apoptosis resistance of senescent human fibroblasts is correlated with the absence of nuclear IGFBP-3. Aging Cell 2005;4:325–30. DOI: https://doi.org/10.1111/j.1474-9726.2005.00180.x
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science 2006;311:1257. DOI: https://doi.org/10.1126/science.1122446
Hoenicke L, Zender L. Immune surveillance of senescent cells-biological significance in cancer-and non-cancer pathologies. Carcinogenesis 2012;33:1123–6. DOI: https://doi.org/10.1093/carcin/bgs124
Marcotte R, Lacelle C, Wang E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev 2004;125:S777–83. DOI: https://doi.org/10.1016/j.mad.2004.07.007
Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, Van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016;354:472-7. DOI: https://doi.org/10.1126/science.aaf6659
Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009;15:1082-7. DOI: https://doi.org/10.1038/nm.2014
Moncsek A, Al-Suraih MS, Trussoni CE, O’Hara SP, Splinter PL, Zuber C, et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice. Hepatology 2018;67:247–59. DOI: https://doi.org/10.1002/hep.29464
Pompili S, Sferra R, Gaudio E, Viscido A, Frieri G, Vetuschi A, et al. Can Nrf2 modulate the development of intestinal fibrosis and cancer in inflammatory bowel disease? Int J Mol Sci 2019;20:4061. DOI: https://doi.org/10.3390/ijms20164061
Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 2017;8:15691. DOI: https://doi.org/10.1038/ncomms15691
Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis. JAMA 2020;323:1175. DOI: https://doi.org/10.1001/jama.2020.2298
Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019;16:411–28. DOI: https://doi.org/10.1038/s41575-019-0145-7
Pompili S, Vetuschi A, Gaudio E, Tessitore A, Capelli R, Alesse E, et al. Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH. Nutrition 2020;75-76:10782. DOI: https://doi.org/10.1016/j.nut.2020.110782
Tessitore A, Mastroiaco V, Vetuschi A, Sferra R, Pompili S, Cicciarelli G, et al. Development of hepatocellular cancer induced by long term low fat-high carbohydrate diet in a NAFLD/NASH mouse model. Oncotarget 2017;8:53482–94. DOI: https://doi.org/10.18632/oncotarget.18585
Schade M, Sanabria JJ, Aguilar R, Modarresi M, Gillon B, Hunter Z, et al. Cellular senescence and their role in liver metabolism in health and disease: Overview and future directions. World J Surg Surg Res 2018;1:1035-51. DOI: https://doi.org/10.5772/intechopen.71659
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060-72. DOI: https://doi.org/10.1016/j.cell.2012.03.042
Cillero-Pastor B, Caramés B, Lires-Deán M, Vaamonde-García C, Blanco FJ, López-Armada MJ. Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes. Arthritis Rheum 2008;58:2409-19. DOI: https://doi.org/10.1002/art.23644
Lei P, Bai T, Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: A review. Front Physiol 2019;10:139. DOI: https://doi.org/10.3389/fphys.2019.00139
Li J, Cao F, Yin H liang, Huang Z jian, Lin Z tao, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis 2020;11:88. DOI: https://doi.org/10.1038/s41419-020-2298-2
Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol 2016;26:165-76. DOI: https://doi.org/10.1016/j.tcb.2015.10.014
Tuo Q, Lei P, Jackman KA, Li X, Xiong H, Li X, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 2017;22:1520-30. DOI: https://doi.org/10.1038/mp.2017.171
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017;171:273-85. DOI: https://doi.org/10.1016/j.cell.2017.09.021
Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017;547:453-7. DOI: https://doi.org/10.1038/nature23007
Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009;51:918–24. DOI: https://doi.org/10.1016/j.jhep.2009.05.033
Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 2008;22:811-6. DOI: https://doi.org/10.1155/2008/810961
Neuschwander-Tetri BA. Carbohydrate intake and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metabol Care 2013;16: 446–52. DOI: https://doi.org/10.1097/MCO.0b013e328361c4d1
Radhakrishnan S, Ke J-Y, Pellizzon MA. Targeted nutrient modifications in purified diets differentially affect nonalcoholic fatty liver disease and metabolic disease development in rodent models. Curr Dev Nutr 2020;4:nzaa078. DOI: https://doi.org/10.1093/cdn/nzaa078
Sferra R, Pompili S, Cappariello A, Gaudio E, Latella G, Vetuschi A. Prolonged chronic consumption of a high fat with sucrose diet alters the morphology of the small intestine. Int J Mol Sci 2021;22:7280–94. DOI: https://doi.org/10.3390/ijms22147280
Velázquez KT, Enos RT, Bader JE, Sougiannis AT, Carson MS, Chatzistamou I, et al. Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice. World J Hepatol 2019;11:619–37. DOI: https://doi.org/10.4254/wjh.v11.i8.619
Tsurusaki S, Tsuchiya Y, Koumura T, Nakasone M, Sakamoto T, Matsuoka M, et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis 2019;10:1-14. DOI: https://doi.org/10.1038/s41419-019-1678-y
Clapper JR, Hendricks MD, Gu G, Wittmer C, Dolman CS, Herich J, et al. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am J Physiol Gastrointest Liver Physiol 2013;305:483–95. DOI: https://doi.org/10.1152/ajpgi.00079.2013
Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today 2017;22:1707-18. DOI: https://doi.org/10.1016/j.drudis.2017.06.007
Kristiansen MNB, Veidal SS, Rigbolt KTG, Tølbøl KS, Roth JD, Jelsing J, et al. Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy. World J Hepatol 2016;8:673–84. DOI: https://doi.org/10.4254/wjh.v8.i16.673
Mells JE, Fu PP, Kumar P, Smith T, Karpen SJ, Anania FA. Saturated fat and cholesterol are critical to inducing murine metabolic syndrome with robust nonalcoholic steatohepatitis. J Nutr Biochem 2015;26:285-92. DOI: https://doi.org/10.1016/j.jnutbio.2014.11.002
Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 2008;295:987-95. DOI: https://doi.org/10.1152/ajpgi.90272.2008
Kleiner DE, Brunt EM, Natta M Van, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–21. DOI: https://doi.org/10.1002/hep.20701
Bedossa P, Poitou C, Veyrie N, Bouillot J-LL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012;56:1751–9. DOI: https://doi.org/10.1002/hep.25889
Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: Defining a path forward. Cell 2019;179:813-27. DOI: https://doi.org/10.1016/j.cell.2019.10.005
Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med 2020;288:518-36. DOI: https://doi.org/10.1111/joim.13141
Qi J, Kim JW, Zhou Z, Lim CW, Kim B. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation -Mediated cell death in mice. Am J Pathol 2020;190:68-81. DOI: https://doi.org/10.1016/j.ajpath.2019.09.011

How to Cite

Vetuschi, A., Cappariello, A., Onori, P., Gaudio, E. ., Latella, G., Pompili, S., & Sferra, R. (2022). Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. European Journal of Histochemistry, 66(3). https://doi.org/10.4081/ejh.2022.3391
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