Browse > Article
http://dx.doi.org/10.5352/JLS.2009.19.8.1119

The Involvement of p38 MAPK and JNK Activation in Palmitic Acid-Induced Apoptosis in Rat Hepatocytes  

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)
Publication Information
Journal of Life Science / v.19, no.8, 2009 , pp. 1119-1124 More about this Journal
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.
Keywords
Hepatocyte; palmitic acid; apoptosis; JNK; p38 MAPK; oxidative stress;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Singh, R. and M. J. Czaja. 2007. Regulation of hepatocyte apoptosis by oxidative stress. J. Gastroenterol. Hepatol. 22 Suppl 1, S45-48
2 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   DOI   ScienceOn
3 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   DOI   ScienceOn
4 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   DOI   ScienceOn
5 Clark, J. M., F. 1. Brancati, and A M. Diehl. 2002. Nonalcoholic fatty liver disease. Gastroenterology 122, 1649-1657   DOI   ScienceOn
6 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   DOI   ScienceOn
7 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   DOI   ScienceOn
8 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   DOI   ScienceOn
9 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   DOI   ScienceOn
10 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   DOI   ScienceOn
11 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   DOI   ScienceOn
12 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-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47, 1905-1915   DOI   ScienceOn
13 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
14 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 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes 49, 1468-1476   DOI   ScienceOn
15 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   DOI   ScienceOn
16 Adiels, M., M. R. Taskinen, and J. Boren. 2008. Fatty liver, insulin resistance, and dyslipidemia. Curro Diab. Rep. 8, 60-64   DOI   ScienceOn
17 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
18 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   DOI   ScienceOn
19 Kowluru, R. A. and S. N. Abbas. 2003. Diabetes-induced mitochondrial dysfunction in the retina. Invest. Ophthalmol. Vis. Sci. 44, 5327-5334   DOI   ScienceOn
20 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   DOI   ScienceOn
21 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   DOI   ScienceOn
22 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   DOI   ScienceOn
23 Ohkawa, H, N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95, 351-358   DOI   ScienceOn
24 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   DOI   ScienceOn
25 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   DOI   ScienceOn
26 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   DOI   ScienceOn
27 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   DOI   ScienceOn