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A pilot study of the onset of hepatic encephalopathy (OHE) in mice induced by thioacetamide and the protective effect of taurine by holistic metabolic characterization

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Abstract

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication due to acute or chronic liver failure. In this work, an acute thioacetamide induced HE mice model was established to investigate the metabolic events in the onset of HE (OHE) and the protective role of taurine (TAU). Sera for biochemical evaluation, and livers and cortexes for histopathological inspection and NMR-based metabolomic investigation were collected. Principal component analysis and orthogonal partial least squares-discriminant analysis were performed to excavate differential metabolites of OHE, and explore the protective role of TAU. Metabolites pathway analysis was performed on significant metabolites selected based on loading/S-plots and fold change plots to identify biologically meaningful metabolic patterns and relevant pathways. The most affected pathways in OHE mice were those along the liver–brain axis: among them, the alanine, aspartate and glutamate metabolism was the most important. TAU showed better performance in improving the disturbed metabolism in the cortex than in the liver of OHE mice. This pilot study based on metabolomics approach and pathway analysis should help to understand HE systematically, and to develop new therapy for HE.

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References

  • Ahboucha, S., & Butterworth, R. F. (2004). Pathophysiology of hepatic encephalopathy: A new look at GABA from the molecular standpoint. Metabolic Brain Disease, 19, 331–343.

    Article  CAS  PubMed  Google Scholar 

  • Akira, K., Hichiya, H., Morita, M., Shimizu, A., & Mitome, H. (2013). Metabonomic study on the biochemical response of spontaneously hypertensive rats to chronic taurine supplementation using 1H NMR spectroscopic urinalysis. Journal of Pharmaceutical and Biomedical Analysis, 85, 155–161.

    Article  CAS  PubMed  Google Scholar 

  • Anderson, P., Mahle, D., Doom, T., Reo, N., DelRaso, N., & Raymer, M. (2011). Dynamic adaptive binning: An improved quantification technique for NMR spectroscopic data. Metabolomics, 7, 179–190.

    Article  CAS  Google Scholar 

  • Asha, K., & Devadasan, K. (2013). Protective effect of taurine on the mitochondria of albino rats induced with fulminant hepatic failure. Biomedicine & Preventive Nutrition, 3, 279–283.

    Article  Google Scholar 

  • Avraham, Y., Grigoriadis, N., Poutahidis, T., Vorobiev, L., Magen, I., Ilan, Y., et al. (2011). Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. British Journal of Pharmacology, 162, 1650–1658.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Avraham, Y., Israeli, E., Gabbay, E., Okun, A., Zolotarev, O., Silberman, I., et al. (2006). Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Neurobiology of Diseases, 21, 237–245.

    Article  CAS  Google Scholar 

  • Avraham, Y., Zolotarev, O., Grigoriadis, N. C., Pautahidis, T., Magen, I., Vorobiav, L., et al. (2008). Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice. The American Journal of Gastroenterology, 103, 3047–3056.

    Article  CAS  PubMed  Google Scholar 

  • Balkan, J., Dogğru-Abbasoğlul, S., Çevikbas, U., Aykaç-Toker, G., & Uysal, M. (2001). Taurine has a protective effect against thioacetamide-induced liver cirrhosis by decreasing oxidative stress. Human and Experimental Toxicology, 20, 251–254.

    Article  CAS  PubMed  Google Scholar 

  • Barba, I., Chatauret, N., García-Dorado, D., & Cordoba, J. (2008). A 1H nuclear magnetic resonance-based metabonomic approach for grading hepatic encephalopathy and monitoring the effects of therapeutic hypothermia in rats. Liver International, 28, 1141–1148.

    Article  CAS  PubMed  Google Scholar 

  • Beckonert, O., Keun, H. C., Ebbels, T. M., Bundy, J., Holmes, E., Lindon, J. C., et al. (2007). Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nature Protocols, 2, 2692–2703.

    Article  CAS  PubMed  Google Scholar 

  • Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B, 57, 289–300.

    Google Scholar 

  • Bergeron, M., Layrargues, G. P., & Butterworth, R. F. (1989). Aromatic and branched-chain amino acids in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Metabolic Brain Disease, 4, 169–176.

    Article  CAS  PubMed  Google Scholar 

  • Blei, A. T., & Córdoba, J. (2001). Hepatic encephalopathy. The American Journal of Gastroenterology, 96, 1968–1976.

    Article  CAS  PubMed  Google Scholar 

  • Boca, S. M., Sinha, R., Cross, A. J., Moore, S. C., & Sampson, J. N. (2014). Testing multiple biological mediators simultaneously. Bioinformatics, 30, 214–220.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bruck, R., Oren, R., Shirin, H., Aeed, H., Papa, M., Matas, Z., et al. (1998). Hypothyroidism minimizes liver damage and improves survival in rats with thioacetamide induced fulminant hepatic failure. Hepatology, 27, 1013–1020.

    Article  CAS  PubMed  Google Scholar 

  • Butterworth, R. F. (1996a). Neuroactive amino acids in hepatic encephalopathy. Metabolic Brain Disease, 11, 165–173.

    Article  CAS  PubMed  Google Scholar 

  • Butterworth, R. F. (1996b). Taurine in hepatic encephalopathy. Advances in Experimental Medicine and Biology, 403, 601–606.

    Article  CAS  PubMed  Google Scholar 

  • Butterworth, R. F. (2002). Pathophysiology of hepatic encephalopathy: A new look at ammonia. Metabolic Brain Disease, 17, 221–227.

    Article  CAS  PubMed  Google Scholar 

  • Butterworth, R. F., Lavoie, J., Giguere, J. F., Layrargues, G. P., & Bergeron, M. (1987). Cerebral GABA-ergic and glutamatergic function in hepatic encephalopathy. Neurochemical Patholology, 6, 131–144.

    Article  CAS  Google Scholar 

  • Cauli, O., Rodrigo, R., Llansola, M., Montoliu, C., Monfort, P., Piedrafita, B., et al. (2009). Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metabolic Brain Disease, 24, 69–80.

    Article  CAS  PubMed  Google Scholar 

  • Cloarec, O., Dumas, M. E., Trygg, J., Craig, A., Barton, R. H., Lindon, J. C., et al. (2005). Evaluation of the orthogonal projection on latent structure model limitations caused by chemical shift variability and improved visualization of biomarker changes in 1H NMR spectroscopic metabonomic studies. Analytical Chemistry, 77, 517–526.

    Article  CAS  PubMed  Google Scholar 

  • Coen, M., Holmes, E., Lindon, J. C., & Nicholson, J. K. (2008). NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. Chemical Research in Toxicology, 21, 9–27.

    Article  CAS  PubMed  Google Scholar 

  • Cordoba, J., Gottstein, J., & Blei, A. T. (1998). Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. Journal of Hepatology, 29, 589–594.

    Article  CAS  PubMed  Google Scholar 

  • Das, J., Ghosh, J., Manna, P., & Sil, P. C. (2010). Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCδ-JNK pathway. PLoS ONE, 5, 12602–12620.

    Article  Google Scholar 

  • Dieterle, F., Ross, A., Schlotterbeck, G., & Senn, H. (2006). Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Analytical Chemistry, 78, 4281–4290.

    Article  CAS  PubMed  Google Scholar 

  • Dorğru-Abbasoğlu, S., Kanbağli, Ö., Balkan, J., Çevikbaş, U., Aykaç-Tokerl, G., & Uysall, M. (2001). The protective effect of taurine against thioacetamide hepatotoxicity of rats. Human and Experimental Toxicology, 20, 23–27.

    Article  Google Scholar 

  • Ferenci, P., Lockwood, A., Mullen, K., Tarter, R., Weissenborn, K., & Blei, A. T. (2002). Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology, 35, 716–721.

    Article  PubMed  Google Scholar 

  • Fonville, J. M., Richards, S. E., Barton, R. H., Boulange, C. L., Ebbels, T., Nicholson, J. K., et al. (2010). The evolution of partial least squares models and related chemometric approaches in metabonomics and metabolic phenotyping. Journal of Chemometrics, 24, 636–649.

    Article  CAS  Google Scholar 

  • Hammes, T. O., Pedroso, G. L., Hartmann, C. R., Escobar, T. D. C., Fracasso, L. B., da Rosa, D. P., et al. (2012). The effect of taurine on hepatic steatosis induced by thioacetamide in zebrafish (Danio rerio). Digestive Diseases and Sciences, 57, 675–682.

    Article  CAS  PubMed  Google Scholar 

  • Hilgier, W., Zielińska, M., Borkowska, H. D., Gadamski, R., Walski, M., Oja, S. S., et al. (1999). Changes in the extracellular profiles of neuroactive amino acids in the rat striatum at the asymptomatic stage of hepatic failure. Journal of Neuroscience Research, 56, 76–84.

    Article  CAS  PubMed  Google Scholar 

  • Holmes, E., Cloarec, O., & Nicholson, J. (2006). Probing latent biomarker signatures and in vivo pathway activity in experimental disease states via statistical total correlation spectroscopy (STOCSY) of biofluids: Application to HgCl2 toxicity. Journal of Proteome Research, 5, 1313–1320.

    Article  CAS  PubMed  Google Scholar 

  • Izquierdo-García, J. L., Rodríguez, I., Kyriazis, A., Villa, P., Barreiro, P., Desco, M., et al. (2009). A novel R-package graphic user interface for the analysis of metabonomic profiles. BMC Bioinformatics, 10, 363.

    Article  PubMed Central  PubMed  Google Scholar 

  • Jalan, R., Shawcross, D., & Davies, N. (2003). The molecular pathogenesis of hepatic encephalopathy. The International Journal of Biochemistry & Cell Biology, 35, 1175–1181.

    Article  CAS  Google Scholar 

  • Jiménez, B., Montoliu, C., MacIntyre, D. A., Serra, M. A., Wassel, A., Jover, M., et al. (2010). Serum metabolic signature of minimal hepatic encephalopathy by 1H nuclear magnetic resonance. Journal of Proteome Research, 9, 5180–5187.

    Article  PubMed  Google Scholar 

  • Junyent, F., Utrera, J., Romero, R., Pallas, M., Camins, A., Duque, D., et al. (2009). Prevention of epilepsy by taurine treatments in mice experimental model. Journal of Neuroscience Research, 87, 1500–1508.

    Article  CAS  PubMed  Google Scholar 

  • Larsson, S. (1957). Food preferences in obesity caused by goldthioglucose. Acta Physiologica Scandinavica, 40, 367–376.

    Article  CAS  PubMed  Google Scholar 

  • Lindon, J. C., Holmes, E., Bollard, M. E., Stanley, E. G., & Nicholson, J. K. (2004). Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers, 9, 1–31.

    Article  CAS  PubMed  Google Scholar 

  • McPhail, M. J., & Taylor-Robinson, S. D. (2010). The role of magnetic resonance imaging and spectroscopy in hepatic encephalopathy. Metabolic Brain Disease, 25, 65–72.

    Article  PubMed  Google Scholar 

  • Miyazaki, T., & Matsuzaki, Y. (2014). Taurine and liver diseases: A focus on the heterogeneous protective properties of taurine. Amino Acids, 46, 101–110.

    Article  CAS  PubMed  Google Scholar 

  • Nicholson, J., Lindon, J., & Holmes, E. (1999). Metabonomics: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 29, 1181–1189.

    Article  CAS  PubMed  Google Scholar 

  • Norskov, N. P., Hedemann, M. S., Laerke, H. N., & Knudsen, K. E. B. (2013). Multicompartmental nontargeted LC–MS metabolomics: Explorative study on the metabolic responses of rye fiber versus refined wheat fiber intake in plasma and urine of hypercholesterolemic pigs. Journal of Proteome Research, 12, 2818–2832. doi:10.1021/pr400164b.

    Article  PubMed  Google Scholar 

  • Oja, S. S., & Saransaari, P. (2007). Pharmacology of taurine. In: Proceedings-Western Pharmacology Society, (vol 50). Western Pharmacology Society, 1998, pp. 8–15

  • Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanuš, L., Breuer, A., Mechoulam, R., et al. (2001). An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature, 413, 527–531.

    Article  CAS  PubMed  Google Scholar 

  • Riordan, S. M., & Williams, R. (1997). Treatment of hepatic encephalopathy. New England Journal of Medicine, 337, 473–479.

    Article  CAS  PubMed  Google Scholar 

  • Rosemberg, D. B., da Rocha, R. F., Rico, E. P., Zanotto-Filho, A., Dias, R. D., Bogo, M. R., et al. (2010). Taurine prevents enhancement of acetylcholinesterase activity induced by acute ethanol exposure and decreases the level of markers of oxidative stress in zebrafish brain. Neuroscience, 171, 683–692.

    Article  CAS  PubMed  Google Scholar 

  • Saransaari, P., & Oja, S. S. (2000). Taurine and neural cell damage. Amino Acids, 19, 509–526. doi:10.1007/s007260070003.

    Article  CAS  PubMed  Google Scholar 

  • Schauer, N., & Fernie, A. R. (2006). Plant metabolomics: Towards biological function and mechanism. Trends in Plant Science, 11, 508–516.

    Article  CAS  PubMed  Google Scholar 

  • Sergeeva, O. A. (2013). GABAergic transmission in hepatic encephalopathy. Archives of Biochemistry and Biophysics, 536, 122–130.

    Article  CAS  PubMed  Google Scholar 

  • Suarez, I., Bodega, G., & Fernandez, B. (2002). Glutamine synthetase in brain: Effect of ammonia. Neurochemistry International, 41, 123–142.

    Article  CAS  PubMed  Google Scholar 

  • Westerhuis, J., Hoefsloot, H. J., Smit, S., Vis, D., Smilde, A., Velzen, E. J., et al. (2008). Assessment of PLSDA cross validation. Metabolomics, 4, 81–89. doi:10.1007/s11306-007-0099-6.

    Article  CAS  Google Scholar 

  • Wishart, D. S., Jewison, T., Guo, A. C., Wilson, M., Knox, C., Liu, Y., et al. (2013). HMDB 3.0—The Human Metabolome Database in 2013. Nucleic Acids Research, 41, D801–D807. doi:10.1093/nar/gks1065.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wishart, D. S., Knox, C., Guo, A. C., Eisner, R., Young, N., Gautam, B., et al. (2009). HMDB: A knowledgebase for the human metabolome. Nucleic Acids Research, 37, D603–D610.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wishart, D. S., Tzur, D., Knox, C., Eisner, R., Guo, A. C., Young, N., et al. (2007). HMDB: The human metabolome database. Nucleic Acids Research, 35, D521–D526.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xia, J., Mandal, R., Sinelnikov, I. V., Broadhurst, D., & Wishart, D. S. (2012). MetaboAnalyst 2.0—a comprehensive server for metabolomic data analysis. Nucleic Acids Research, 40, W127–W133.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xia, J., Psychogios, N., Young, N., & Wishart, D. S. (2009). MetaboAnalyst: A web server for metabolomic data analysis and interpretation. Nucleic Acids Research, 37, W652–W660.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xia, J., & Wishart, D. S. (2010). MetPA: A web-based metabolomics tool for pathway analysis and visualization. Bioinformatics, 26, 2342–2344.

    Article  CAS  PubMed  Google Scholar 

  • Zeng, K., Xu, H., Chen, K., Zhu, J., Zhou, Y., Zhang, Q., et al. (2010). Effects of taurine on glutamate uptake and degradation in Müller cells under diabetic conditions via antioxidant mechanism. Molecular and Cellular Neuroscience, 45, 192–199.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by National Natural Science Foundation of China (NSFC) Grant 81173526, the Program for New Century Excellent Talents in University (NCET-11-0738), the Fundamental Research Funds for the Central Universities (No. 30920130112014) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1193).

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All the authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People’s Republic of China

    Dan-Dan Wei, Ming-Hui Li, Ping-Ping Guo, Ge Dong, Ming-Hua Yang & Ling-Yi Kong

  2. Center for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei, Nanjing, 210094, People’s Republic of China

    Jun-Song Wang

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  1. Dan-Dan Wei
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Wei, DD., Wang, JS., Li, MH. et al. A pilot study of the onset of hepatic encephalopathy (OHE) in mice induced by thioacetamide and the protective effect of taurine by holistic metabolic characterization. Metabolomics 11, 559–570 (2015). https://doi.org/10.1007/s11306-014-0715-1

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