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Cytotoxic Effect of Triglycerides via Apoptotic Caspase Pathway in Immune and Non-immune Cell Lines

  • Lim, Jaewon (Department of Clinical Laboratory Science, College of Medical Sciences, Daegu Haany University) ;
  • Yang, Eun Ju (Department of Clinical Laboratory Science, College of Medical Sciences, Daegu Haany University) ;
  • Chang, Jeong Hyun (Department of Clinical Laboratory Science, College of Medical Sciences, Daegu Haany University)
  • Received : 2019.01.28
  • Accepted : 2019.03.12
  • Published : 2019.03.31

Abstract

Hyperlipidemia is defined as conditions of the accumulation of lipids such as free fatty acids (FFA), triglyceride (TG), cholesterol and/or phospholipid in the bloodstream. Hyperlipidemia can cause lipid accumulation in non-adipose tissue, which is lipid-cytotoxic effects in many tissues and mediates cell dysfunction, inflammation or programmed cell death (PCD). TG is considered to be a major cause of atherosclerosis through inflammatory necrosis of vascular endothelial cells. Recently, TG have also been shown to exhibit lipid-cytotoxicity and induce PCD. Therefore, we investigated the effect of TG on the cytotoxic effect of various cell types. When exposed to TG, the cell viability of U937 monocytes and Jurkat T lymphocytes, as well as the cell viability of MCF-7, a non-immune cell, decreased in time- and dose-dependent manner. In U937 cells and Jurkat cells, caspase-9, an intrinsic apoptotic caspase, and caspase-8, an extrinsic apoptotic caspase, were increased by exposure to TG. However, in TG-treated MCF-7 cells, caspase-8 activity increased only without caspase-9 activity. In addition, the reduction of cell viability by TG was recovered when all three cell lines were treated with pan-caspase inhibitor. These results suggest that activation of apoptotic caspases by TG causes lipotoxic effect and decreases cell viability.

Keywords

References

  1. Aflaki E, Radovic B, Chandak PG, Kolb D, Eisenberg T, Ring J, Fertschai I, Uellen A, Wolinski H, Kohlwein SD, Zechner R, Levak-Frank S, Sattler W, Graier WF, Malli R, Madeo F, Kratky D. Triacylglycerol accumulation activates the mitochondrial apoptosis pathway in macrophages. J Biol Chem. 2011. 286: 7418-7428. https://doi.org/10.1074/jbc.M110.175703
  2. Aronis A, Madar Z, Tirosh O. Mechanism underlying oxidative stress-mediated lipotoxicity: Exposure of j774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. Free Radic Biol Med. 2005. 38: 1221-1230. https://doi.org/10.1016/j.freeradbiomed.2005.01.015
  3. Aronis A, Madar Z, Tirosh O. Lipotoxic effects of triacylglycerols in j774.2 macrophages. Nutrition. 2008. 24: 167-176. https://doi.org/10.1016/j.nut.2007.10.017
  4. Bosma M, Dapito DH, Drosatos-Tampakaki Z, Huiping-Son N, Huang LS, Kersten S, Drosatos K, Goldberg IJ. Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity. Biochim Biophys Acta. 2014. 1841: 1648-1655. https://doi.org/10.1016/j.bbalip.2014.09.012
  5. Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation. 2004. 109: III2-7. https://doi.org/10.1161/01.CIR.0000110642.73995.BF
  6. Cory S, Adams JM. The bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002. 2: 647-656. https://doi.org/10.1038/nrc883
  7. Cury-Boaventura MF, Gorjao R, de Lima TM, Piva TM, Peres CM, Soriano FG, Curi R. Toxicity of a soybean oil emulsion on human lymphocytes and neutrophils. JPEN J Parenter Enteral Nutr. 2006. 30: 115-123. https://doi.org/10.1177/0148607106030002115
  8. de Vries JE, Vork MM, Roemen TH, de Jong YF, Cleutjens JP, van der Vusse GJ, van Bilsen M. Saturated but not monounsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes. J Lipid Res. 1997. 38: 1384-1394. https://doi.org/10.1016/S0022-2275(20)37421-6
  9. Deveraux QL, Reed JC. Iap family proteins--suppressors of apoptosis. Genes Dev. 1999. 13: 239-252. https://doi.org/10.1101/gad.13.3.239
  10. Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007. 35: 495-516. https://doi.org/10.1080/01926230701320337
  11. Feng B, Zhang D, Kuriakose G, Devlin CM, Kockx M, Tabas I. Niemann-pick c heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis. Proc Natl Acad Sci U S A. 2003. 100: 10423-10428. https://doi.org/10.1073/pnas.1732494100
  12. Fernanda Cury-Boaventura M, Cristine Kanunfre C, Gorjao R, Martins de Lima T, Curi R. Mechanisms involved in jurkat cell death induced by oleic and linoleic acids. Clin Nutr. 2006. 25: 1004-1014. https://doi.org/10.1016/j.clnu.2006.05.008
  13. Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002. 45: 1201-1210. https://doi.org/10.1007/s00125-002-0873-y
  14. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: A meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996. 3: 213-219. https://doi.org/10.1097/00043798-199604000-00014
  15. Johnson ES, Lindblom KR, Robeson A, Stevens RD, Ilkayeva OR, Newgard CB, Kornbluth S, Andersen JL. Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis. J Biol Chem. 2013. 288: 14463-14475. https://doi.org/10.1074/jbc.M112.437210
  16. Kamstrup PR. Lipoprotein(a): The common, likely causal, yet elusive risk factor for cardiovascular disease. J Lipid Res. 2017. 58: 1731-1732. https://doi.org/10.1194/jlr.C079111
  17. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. Cytotoxicity-dependent apo-1 (fas/cd95)-associated proteins form a death-inducing signaling complex (disc) with the receptor. EMBO J. 1995. 14: 5579-5588. https://doi.org/10.1002/j.1460-2075.1995.tb00245.x
  18. Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol. 2000. 157: 1259-1268. https://doi.org/10.1016/S0002-9440(10)64641-X
  19. Kusminski CM, Shetty S, Orci L, Unger RH, Scherer PE. Diabetes and apoptosis: Lipotoxicity. Apoptosis. 2009. 14: 1484-1495. https://doi.org/10.1007/s10495-009-0352-8
  20. Lim J, Kim HK, Kim SH, Rhee KJ, Kim YS. Caspase-2 mediates triglyceride (tg)-induced macrophage cell death. BMB Rep. 2017. 50: 510-515. https://doi.org/10.5483/BMBRep.2017.50.10.106
  21. Lim J, Kim SH, Kang YW, Jung BC, Kim HK, Lee J, Lee D, Rhee KJ, Kim YS. Triglyceride up-regulates expression of abcg1 in pma-induced thp-1 macrophages through activation of jnk and p38 mapk pathways. Biomed Sci Lett. 2014. 20: 237-243. https://doi.org/10.15616/BSL.2014.20.4.237
  22. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV, Jr., Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A. 2003. 100: 3077-3082. https://doi.org/10.1073/pnas.0630588100
  23. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce jnk-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006. 281: 12093-12101. https://doi.org/10.1074/jbc.M510660200
  24. Malloy MJ, Kane JP. A risk factor for atherosclerosis: Triglyceriderich lipoproteins. Adv Intern Med. 2001. 47: 111-136.
  25. Menet R, Bernard M, ElAli A. Hyperlipidemia in stroke pathobiology and therapy: Insights and perspectives. Front Physiol. 2018. 9: 488. https://doi.org/10.3389/fphys.2018.00488
  26. Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol. 2001. 41: 367-401. https://doi.org/10.1146/annurev.pharmtox.41.1.367
  27. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2004. 23: 2861-2874. https://doi.org/10.1038/sj.onc.1207523
  28. Son SJ, Rhee KJ, Lim J, Kim TU, Kim TJ, Kim YS. Triglycerideinduced macrophage cell death is triggered by caspase-1. Biol Pharm Bull. 2013. 36: 108-113. https://doi.org/10.1248/bpb.b12-00571
  29. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag. 2016. 12: 171-183. https://doi.org/10.2147/VHRM.S104369