Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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The Involvement of p38 MAPK and JNK Activation in Palmitic Acid-Induced Apoptosis in Rat Hepatocytes

Palmitic acid에 의한 간세포 사멸효과에 대한 p38 MAPK 및 JNK 관련성

  • Bae, Chun-Sik (Bio-therapy Human Resources Center, Animal Medical Institute, College of Veterinary Medicine, Chonnam National University) ;
  • Park, Soo-Hyun (Bio-therapy Human Resources Center, Animal Medical Institute, College of Veterinary Medicine, Chonnam National University)
  • Published : 2009.08.30
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Abstract

Hyperlipidemia has been reported to be associated with the development of fatty liver. Palmitic acid, a major saturated fatty acid, is involved in the development of diverse diseases. The activation of mitogen activated protein kinases (MAPKs), such as Jun N-terminal kinase (INKs) and p38 MAPK is implicated in the apoptosis in diverse cells. Thus, this study was conducted to investigate the effects of palmitic acid on apoptosis and its relationship between JNK and p38 MAPK in cultured rat hepatocytes. In the present study, palmitic acid (>50 uM) decreased cell proliferation and increased lactate dehydrogenase activity in hepatocytes, which was blocked by the treatment of SP600125 (a JNK inhibitor) and SB203580 (a p38 MAPK inhibitor). Indeed, palmitic acid decreased Bcl-2 expression but increased Bax expression in rat hepatocytes, which was blocked by the treatment of SP600125 and SB203580. In addition, palmitic acid decreased glutathione (GSH) content and increased lipid peroxide formation, which was blocked by the treatment of SP600125 and SB203580. Western immunoblotting analysis also revealed that palmitic acid increased JNK and p38 MAPK. In conclusion, palmitic acid induced apoptosis through oxidative stress via JNK and p38 MAPK activation in rat hepatocytes.

포화 지방산이 인슐린 저항성 및 지방간등의 다양한 질병의 발병에 관련된다고 보고되고 있다. 그러나 간세포에서 포화지방산이 세포 사멸에 대한 효과 및 이와 관련된 신호전달계에 대해서는 거의 알려져 있지 않고 있다. 본 연구에서는 대표적인 포화지방산인 palmitic acid 처리 시 랫트 간세포 사멸에 미치는 효과와 이들이 mitogen activated protein kinases (MAPKs)와 관련되는 지를 알아보았다. 본 실험에서 palmitic acid 처리 시 간세포 성장은 억제 되었고 lactate dehydrogenase (LDH) 활성은 증가하였다. 이러한 작용은 JNK 및 p38 MAPK 억제제에 의해서 선택적으로 차단되었다. 아울러 palmitic acid에 의한 Bcl-2 발현 억제, Bax 발현 증가 작용, GSH 함량 감소작용 및 산화성 스트레스 증가작용 역시 JNK 및 p38 MAPK 억제제에 의해서 선택적으로 차단되었다. 실제로 palmitic acid 처리시 JNK 및 p38 MAPK 활성은 증가하였다. 결론적으로 palmitic acid는 간세포에서 JNK 및 p38 MAPK 활성을 경유하여 산화성 스트레스 증가를 통하여 간세포 사멸을 유도하는 것으로 나타났다.

Keywords

References

  1. Adiels, M., M. R. Taskinen, and J. Boren. 2008. Fatty liver, insulin resistance, and dyslipidemia. Curro Diab. Rep. 8, 60-64 https://doi.org/10.1007/s11892-008-0011-4
  2. Albano, E., M. Rundgren, P. J. Harvison, S. D. Nelson, and P. Moldeus. 1985. Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol. Pharmacol. 28, 306-311
  3. Ammendrup, A, A Maillard, K. Nielsen, N. Aabenhus Andersen, P. Serup, O. Dragsbaek Madsen, T. MandrupPoulsen, and C. Bonny. 2000. The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 andcontrols apoptosis in differentiating pancreatic beta-cells. Diabetes 49, 1468-1476 https://doi.org/10.2337/diabetes.49.9.1468
  4. Anderson, M. E. and A Meister. 1983. Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proc. Natl. A cad. Sci. USA. 80, 707-711 https://doi.org/10.1073/pnas.80.3.707
  5. Becker, E. B., J. Howell, Y. Kodama, P. A Barker, and A Bonni. 2004. Characterization of the c-Jun N-terminal kinase- BimEL signaling pathway in neuronal apoptosis. J. Neurosci. 24, 8762-8770 https://doi.org/10.1523/JNEUROSCI.2953-04.2004
  6. Bradbury, M. W. 2006. Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am. J. Physiol. Gas troin test. Liver Physiol. 290, G194-198 https://doi.org/10.1152/ajpgi.00413.2005
  7. Bradford, M. M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254 https://doi.org/10.1016/0003-2697(76)90527-3
  8. Cao, W., Q. F. Collins, T. C. Becker, J. Robidoux, E. G. Lupo, K. W. Daniel, 1. Floering, and S. Collins. 2005. p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J. BioI. Chem. 280, 42731-42737 https://doi.org/10.1074/jbc.M506223200
  9. Clark, J. M., F. 1. Brancati, and A M. Diehl. 2002. Nonalcoholic fatty liver disease. Gastroenterology 122, 1649-1657 https://doi.org/10.1053/gast.2002.33573
  10. Collins, Q. F., Y Xiong, E. G. Lupo, H Y Liu, and W. Cao. 2006. p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J. BioI. Chem. 281, 24336-24344 https://doi.org/10.1074/jbc.M602177200
  11. Dickinson, D. A. and H. J. Forman. 2002. Glutathione in defense and signaling: lessons from a small thiol. Ann. N. Y. Acad. Sci. 973, 488-504 https://doi.org/10.1111/j.1749-6632.2002.tb04690.x
  12. Guo, W., S. Wong, W. Xie, T. Lei, and Z. Luo. 2007. Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes. Am. J. Physiol.Endocrinol. Metab. 293, E576-586 https://doi.org/10.1152/ajpendo.00523.2006
  13. Joshi-Barve, S., S. S. Barve, K. Amancherla, 1. Gobejishvili, D. HilL M. Cave, P. Hote, and C. J. McClain. 2007. Palmitic acid induces production of proinflammatory cytokine interleukin- 8 from hepatocytes. Hepatology 46, 823-830 https://doi.org/10.1002/hep.21752
  14. Kim, B. L s. W. Ryu, and B. Song. 2006. JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J. BioI. Chem. 281, 21256-21265 https://doi.org/10.1074/jbc.M510644200
  15. Kowluru, R. A. and S. N. Abbas. 2003. Diabetes-induced mitochondrial dysfunction in the retina. Invest. Ophthalmol. Vis. Sci. 44, 5327-5334 https://doi.org/10.1167/iovs.03-0353
  16. Larter, C. Z., M. M. Yeh, W. G. Haigh, J. Williams, S. Brown, K. S. Bell-Anderson, S. P. Lee, and G. C. Farrell. 2008. Hepatic free fatty acids accumulate in experimental steatohepatitis: role of adaptive pathways. J. Hepatol. 48, 638-647 https://doi.org/10.1016/j.jhep.2007.12.011
  17. Lin, H. H, J. H Chen, W. H. Kuo, and C. J. Wang. 2007. Chemopreventive properties of Hibiscus sabdariffa 1. on human gastric carcinoma cells through apoptosis induction and JNK/ p38 MAPK signaling activation. Chem. BioI. Interact. 165, 59-75 https://doi.org/10.1016/j.cbi.2006.10.011
  18. Malhi, H, S. F. Bronk, N. W. Werneburg, and G. J. Gores. 2006. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J. BioI. Chem. 281, 12093-12101 https://doi.org/10.1074/jbc.M510660200
  19. Marceau, P., S. Biron, F. S. Hould, S. Marceau, S. Simard, S. N. Thung, and J. G. Kral. 1999. Liver pathology and the metabolic syndrome X in severe obesity. J. Clin. Endocrinol. Metab. 84, 1513-1517 https://doi.org/10.1210/jc.84.5.1513
  20. Ohkawa, H, N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95, 351-358 https://doi.org/10.1016/0003-2697(79)90738-3
  21. Reid, B. N., G. P. Ables, O. A. Otlivanchik G. SchoiswohL R. Zechner, W. S. Blaner, I. J. Goldberg, R. F. Schwabe, S. C. Chua Jr, and 1. S. Huang. 2008. Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J. BioI. Chem. 283, 13087-13099 https://doi.org/10.1074/jbc.M800533200
  22. Sharifi, A. M., S. H Mousavi, M. Farhadi, and B. Larijani. 2007. Study of high glucose-induced apoptosis in PC12 cells: role of bax protein. J. Pharmacol. Sci. 104, 258-262 https://doi.org/10.1254/jphs.FP0070258
  23. Singh, R. and M. J. Czaja. 2007. Regulation of hepatocyte apoptosis by oxidative stress. J. Gastroenterol. Hepatol. 22 Suppl 1, S45-48
  24. Suzuki, T. and I. Tsukamoto. 2006. Arsenite induces apoptosis in hepatocytes through an enhancement of the activation of Jun N-terminal kinase and p38 mitogen-activated protein kinase caused by partial hepatectomy. Toxicol. Lett. 165, 257-264 https://doi.org/10.1016/j.toxlet.2006.05.004
  25. Wei, Y, D. Wang, F. Topczewski, and M. J. Pagliassotti. 2006. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. Endocrinol. Metab. 291, E275-281 https://doi.org/10.1152/ajpendo.00644.2005
  26. Wu, X., 1. Zhang, E. Gurley, E. Studer, J. Shang, T. Wang, C. Wang, M. Yan, Z. Jiang, P. B. Hylemon, A. J. SanyaL W. M. Pandak Jr, and H. Zhou. 2008. Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinicacid through lysosomal and mitochondrial pathways. Hepatology 47, 1905-1915 https://doi.org/10.1002/hep.22239
  27. Yazihan, N., H Ataolu, B. Yener, and C. Aydin. 2007. Erythropoietin attenuates hydrogen peroxide-induced damage of hepatocytes. Turk. J. Gas troen terol. 18, 239-244

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