Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Enhanced Production of Adenosine Triphosphate by Pharmacological Activation of Adenosine Monophosphate-Activated Protein Kinase Ameliorates Acetaminophen-Induced Liver Injury

  • Hwang, Jung Hwan (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST)) ;
  • Kim, Yong-Hoon (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST)) ;
  • Noh, Jung-Ran (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST)) ;
  • Choi, Dong-Hee (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST)) ;
  • Kim, Kyoung-Shim (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST)) ;
  • Lee, Chul-Ho (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology (UST))
  • Received : 2015.03.17
  • Accepted : 2015.07.01
  • Published : 2015.10.31
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Abstract

The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.

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References

  1. Cohen, S.D., and Khairallah, E.A. (1997). Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab. Rev. 29, 59-77. https://doi.org/10.3109/03602539709037573
  2. Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R., et al. (2006). Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403-416. https://doi.org/10.1016/j.cmet.2006.05.005
  3. Dahlin, D.C., Miwa, G.T., Lu, A.Y., and Nelson, S.D. (1984). Nacetyl- p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. USA 81, 1327-1331. https://doi.org/10.1073/pnas.81.5.1327
  4. Dong, G.Z., Lee, J.H., Ki, S.H., Yang, J.H., Cho, I.J., Kang, S.H., Zhao, R.J., Kim, S.C., and Kim, Y.W., (2014). AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction. Eur. J. Pharmacol. 740, 634-640. https://doi.org/10.1016/j.ejphar.2014.06.017
  5. Fogarty, S., and Hardie, D.G. (2010). Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim. Biophys. Acta 1804, 581-591. https://doi.org/10.1016/j.bbapap.2009.09.012
  6. Goransson, O., McBride, A., Hawley, S.A., Ross, F.A., Shpiro, N., Foretz, M., Viollet, B., Hardie, D.G., and Sakamoto, K. (2007). Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282, 32549-32560. https://doi.org/10.1074/jbc.M706536200
  7. Hardie, D.G., and Sakamoto, K. (2006). AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology 21, 48-60. https://doi.org/10.1152/physiol.00044.2005
  8. Hinson, J.A., Roberts, D.W., and James, L.P. (2010). Mechanisms of acetaminophen-induced liver necrosis. Handb. Exp. Pharmacol. 2010, 369-405.
  9. Hwang, J.H., Kim, Y.H., Noh, J.R., Gang, G.T., Kim, K.S., Chung, H.K., Tadi, S., Yim, Y.H., Shong, M., and Lee, C.H. (2014). The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction. Arch. Toxicol. [Epub ahead of print].
  10. Ido, Y., Carling, D., and Ruderman, N. (2002). Hyperglycemiainduced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51, 159-167. https://doi.org/10.2337/diabetes.51.1.159
  11. Jaeschke, H., and Bajt, M.L. (2006). Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol. Sci. 89, 31-41. https://doi.org/10.1093/toxsci/kfi336
  12. Jia, F., Wu, C., Chen, Z., Lu, G. (2011). AMP-activated protein kinase inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells. Cardiovasc. Drugs Ther. 25, 21-25. https://doi.org/10.1007/s10557-010-6277-1
  13. Jia, F., Wu, C., Chen, Z., Lu, G. (2012). Atorvastatin inhibits homocysteine-induced endoplasmic reticulum stress through activation of AMP-activated protein kinase. Cardiovasc. Ther. 30, 317-325. https://doi.org/10.1111/j.1755-5922.2011.00287.x
  14. Jung, Y., Jang, Y.J., Kang, M.H., Park, Y.S., Oh, S.J., Lee, D.C., Xie, Z., Yoo, H.S., Park, K. C., Yeom, Y.I., (2013). Metabolic signature genes associated with susceptibility to pyruvate kinase, muscle type 2 gene ablation in cancer cells. Mol. Cells 35, 335-341. https://doi.org/10.1007/s10059-013-2319-4
  15. Larson, A.M., Polson, J., Fontana, R.J., Davern, T.J., Lalani, E., Hynan, L.S., Reisch, J.S., Schiodt, F.V., Ostapowicz, G., Shakil, A.O., et al. (2005). Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42, 1364-1372. https://doi.org/10.1002/hep.20948
  16. McGill, M.R., Williams, C.D., Xie, Y., Ramachandran, A., and Jaeschke, H. (2012). Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol. Appl. Pharmacol. 264, 387-394. https://doi.org/10.1016/j.taap.2012.08.015
  17. Mihaylova, M.M., and Shaw, R.J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016-1023. https://doi.org/10.1038/ncb2329
  18. Nelson, S.D. (1990). Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin. Liver Dis. 10, 267-278. https://doi.org/10.1055/s-2008-1040482
  19. Nieminen, A.L., Saylor, A.K., Herman, B., and Lemasters, J.J. (1994). ATP depletion rather than mitochondrial depolarization mediates hepatocyte killing after metabolic inhibition. Am. J. Physiol. 267, C67-74. https://doi.org/10.1152/ajpcell.1994.267.1.C67
  20. Packer, M.A., Scarlett, J.L., Martin, S.W., and Murphy, M.P. (1997). Induction of the mitochondrial permeability transition by peroxynitrite. Biochem. Soc. Trans. 25, 909-914. https://doi.org/10.1042/bst0250909
  21. Peralta, C., Bartrons, R., Serafin, A., Blazquez, C., Guzman, M., Prats, N., Xaus, C., Cutillas, B., Gelpi, E., and Rosello-Catafau, J. (2001). Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat. Hepatology 34, 1164-1173. https://doi.org/10.1053/jhep.2001.29197
  22. Polson, J., and Lee, W.M. (2005). AASLD position paper: the management of acute liver failure. Hepatology 41, 1179-1197. https://doi.org/10.1002/hep.20703
  23. Qian, T., Herman, B., and Lemasters, J.J. (1999). The mitochondrial permeability transition mediates both necrotic and apoptotic death of hepatocytes exposed to Br-A23187. Toxicol. Appl. Pharmacol. 154, 117-125. https://doi.org/10.1006/taap.1998.8580
  24. Qiu, G., Wan, R., Hu, J., Mattson, M.P., Spangler, E., Liu, S., Liu, S., Yau, S.-Y., Lee, T.M.C., Gleichmann, M., et al. (2011). Adiponectin protects rat hippocampal neurons against excitotoxicity. Age 33, 155-165. https://doi.org/10.1007/s11357-010-9173-5
  25. Rossi, A., and Lord, J.M. (2013). Adiponectin inhibits neutrophil apoptosis via activation of AMP kinase, PKB and ERK 1/2 MAP kinase. Apoptosis 18, 1469-1480. https://doi.org/10.1007/s10495-013-0893-8
  26. Saberi, B., Ybanez, M.D., Johnson, H.S., Gaarde, W.A., Han, D., and Kaplowitz, N. (2014). Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways. Hepatology 59, 1543-1554. https://doi.org/10.1002/hep.26625
  27. Saito, C., Lemasters, J.J., and Jaeschke, H. (2010). c-Jun Nterminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol. Appl. Pharmacol. 246, 8-17. https://doi.org/10.1016/j.taap.2010.04.015
  28. Sanders, M.J., Ali, Z.S., Hegarty, B.D., Heath, R., Snowden, M.A., and Carling, D. (2007). Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem. 282, 32539-32548. https://doi.org/10.1074/jbc.M706543200
  29. Shin, S.M., Cho, I.J., and Kim, S.G. (2009). Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol. Pharmacol. 76, 884-895. https://doi.org/10.1124/mol.109.058479
  30. Stefanelli, C., Stanic, I., Bonavita, F., Flamigni, F., Pignatti, C., Guarnieri, C., and Caldarera, C.M. (1998). Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMPactivated protein kinase. Biochem. Biophys. Res. Commun. 243, 821-826. https://doi.org/10.1006/bbrc.1998.8154
  31. Steinberg, G.R., and Kemp, B.E. (2009). AMPK in health and disease. Physiol. Rev. 89, 1025-1078. https://doi.org/10.1152/physrev.00011.2008
  32. Towler, M.C., and Hardie, D.G. (2007). AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res. 100, 328-341. https://doi.org/10.1161/01.RES.0000256090.42690.05
  33. Viollet, B., Athea, Y., Mounier, R., Guigas, B., Zarrinpashneh, E., Horman, S., Lantier, L., Hebrard, S., Devin-Leclerc, J., Beauloye, C., et al. (2009). AMPK: Lessons from transgenic and knockout animals. Front Biosci. 14, 19-44.
  34. Yang, Y.M., Han, C.Y., Kim, Y.J., and Kim, S.G. (2010). AMPKassociated signaling to bridge the gap between fuel metabolism and hepatocyte viability. World J. Gastroenterol. 16, 3731-3742. https://doi.org/10.3748/wjg.v16.i30.3731

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