Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature

Abstract

Introduction

Wilson disease (WD) is characterized by excessive intracellular copper accumulation in liver and brain due to defective copper biliary excretion. With highly varied phenotypes and a lack of biomarkers for the different clinical manifestations, diagnosis and treatment can be difficult.

Objective

The aim of the present study was to analyze serum metabolomics profiles of patients with Wilson disease compared to healthy subjects, with the goal of identifying differentially abundant metabolites as potential biomarkers for this condition.

Methods

Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry was used to evaluate the untargeted serum metabolome of 61 patients with WD (26 hepatic and 25 neurologic subtypes, 10 preclinical) compared to 15 healthy subjects. We conducted analysis of covariance with potential confounders (body mass index, age, sex) as covariates and partial least-squares analysis.

Results

After adjusting for clinical covariates and multiple testing, we identified 99 significantly different metabolites (FDR < 0.05) between WD and healthy subjects. Subtype comparisons also revealed significantly different metabolites compared to healthy subjects: WD hepatic subtype (67), WD neurologic subtype (57), WD hepatic-neurologic combined (77), and preclinical (36). Pathway analysis revealed these metabolites are involved in amino acid metabolism, the tricarboxylic acid cycle, choline metabolism, and oxidative stress.

Conclusions

Patients with WD are characterized by a distinct metabolomics profile providing new insights into WD pathogenesis and identifying new potential diagnostic biomarkers.

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Data availability

The metabolomics and metadata reported in this paper are available via Metabolomics Workbench http://www.metabolomicsworkbench.org/, and study can be found under ST001118.

Change history

  • 03 December 2019

    In the originally published version of this article, there was an error. The metabolomics platform used for the analysis is GC-TOF-MS, Gas Chromatography Time-of-Flight Mass Spectrometry and not Hydrophilic Interaction Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry as indicated in the original version.

Abbreviations

WD:

Wilson disease

HILIC-QTOF MS:

Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry

PLS-LDA:

Partial least-squares regression with linear discriminant analysis

FDR:

False discovery rate

TCA:

Tricarboxylic acid

HN:

Hepatic-neurologic manifestations combined

GSH:

Glutathione

GR:

Glucocorticoid receptor

PDH:

Pyruvate dehydrogenase

ROS:

Reactive oxygen species

2-HBA:

2-Hydroxybutanoic acid

AA:

Ascorbic acid

IPA:

Indole-3-proprionic acid

References

  1. Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., & Schilsky, M. L. (2007). Wilson’s disease. The Lancet, 369, 397–408.

    CAS  Google Scholar 

  2. Aliasgharpour, M. (2015). A review on copper, ceruloplasmin and Wilson’s disease. International Journal of Medical Investigation, 4(4), 344–347.

    CAS  Google Scholar 

  3. Alonso, C., Fernandez-Ramos, D., Varela-Rey, M., Martinez-Arranz, I., Navasa, N., Van Liempd, S. M., Lavin Trueba, J. L., Mayo, R., Ilisso, C. P., de Juan, V. G., Iruarrizaga-Lejarreta, M., delaCruz-Villar, L., Minchole, I., Robinson, A., Crespo, J., Martin-Duce, A., Romero-Gomez, M., Sann, H., Platon, J., Van Eyk, J., Aspichueta, P., Noureddin, M., Falcon-Perez, J. M., Anguita, J., Aransay, A. M., Martinez-Chantar, M. L., Lu, S. C., & Mato, J. M. (2017) Metabolomic identification of subtypes of nonalcoholic steatohepatitis. Gastroenterology, 152, 1449–1461.e7.

    PubMed  PubMed Central  Google Scholar 

  4. Ames, B. N., Cathcart, R., Schwiers, E., & Hochstein, P. (1981). Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: A hypothesis. Proceedings of National Academy of Sciences of United States of America, 78, 6858–6862.

    CAS  Google Scholar 

  5. Attri, S., Sharma, N., Jahagirdar, S., Thapa, B. R., & Prasad, R. (2006). Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. Pediatric Research, 59, 593–597.

    CAS  PubMed  Google Scholar 

  6. Baker, D. H., & Czarnecki-Maulden, G. L. (1987). Pharmacologic role of cysteine in ameliorating or exacerbating mineral toxicities. Journal of Nutrition, 117, 1003–1010.

    CAS  PubMed  Google Scholar 

  7. Banasch, M., Goetze, O., Knyhala, K., Potthoff, A., Schlottmann, R., Kwiatek, M. A., Bulut, K., Schmitz, F., Schmidt, W. E., & Brockmeyer, N. H. (2006). Uridine supplementation enhances hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients. AIDS, 20, 1554–1556.

    CAS  PubMed  Google Scholar 

  8. Brancaccio, D., Gallo, A., Piccioli, M., Novellino, E., Ciofi-Baffoni, S., & Banci, L. (2017). [4Fe-4S] Cluster assembly in mitochondria and its impairment by copper. Journal of the American Chemical Society, 139, 719–730.

    Google Scholar 

  9. Braymer, J. J., & Lill, R. (2017). Iron-sulfur cluster biogenesis and trafficking in mitochondria. Journal of Biological Chemistry, 292, 12754–12763.

    CAS  PubMed  Google Scholar 

  10. Briggs, J., Finch, P., Matulewicz, M. C., & Weigel, H. (1981). Complexes of copper(II), calcium, and other metal ions with carbohydrates: Thin-layer ligand-exchange chromatography and determination of relative stabilities of complexes. Carbohydrate Research, 97, 181–188.

    CAS  Google Scholar 

  11. Bull, P. C., Thomas, G. R., Rommens, J. M., Forbes, J. R., & Cox, D. W. (1993). The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics, 5, 327–337.

    CAS  PubMed  Google Scholar 

  12. Cabras, T., Sanna, M., Manconi, B., Fanni, D., Demelia, L., Sorbello, O., Iavarone, F., Castagnola, M., Faa, G., & Messana, I. (2015). Proteomic investigation of whole saliva in Wilson’s disease. Journal of Proteomics, 128, 154–163.

    CAS  PubMed  Google Scholar 

  13. Chen, Y., Yang, Y., Miller, M. L., Shen, D., Shertzer, H. G., Stringer, K. F., Wang, B., Schneider, S. N., Nebert, D. W., & Dalton, T. P. (2007). Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology, 45, 1118–1128.

    CAS  PubMed  Google Scholar 

  14. Chinnasamy, T., Sharma, Y., Gupta, P., & Gupta, S. (2016) Arsenic (As) and Copper (Cu) serve as cofactors to produce hepatotoxicity with mitochondrial damage, double strand DNA breaks and disruption of ATM signaling. The FASEB Journal, 30, 1026.3.

    Google Scholar 

  15. Chong, A. S., Huang, W., Liu, W., Luo, J., Shen, J., Xu, W., Ma, L., Blinder, L., Xiao, F., Xu, X., Clardy, C., Foster, P., & Williams, J. A. (1999). In vivo activity of leflunomide: Pharmacokinetic analyses and mechanism of immunosuppression. Transplantation, 68, 100–109.

    CAS  PubMed  Google Scholar 

  16. Czlonkowska, A., Litwin, T., Dusek, P., Ferenci, P., Lutsenko, S., Medici, V., Rybakowski, J. K., Weiss, K. H., & Schilsky, M. L. (2018). Wilson disease. Nature Review Disease Primers, 4, 21.

    Google Scholar 

  17. Droge, W. (2005). Oxidative stress and ageing: Is ageing a cysteine deficiency syndrome? Philosophical Transactions of Royal Society London. Series B, Biological Sciences, 360, 2355–2372.

    Google Scholar 

  18. Eriksson, U. J., Naeser, P., & Brolin, S. E. (1986). Increased accumulation of sorbitol in offspring of manifest diabetic rats. Diabetes, 35, 1356–1363.

    CAS  PubMed  Google Scholar 

  19. Ferenci, P., Caca, K., Loudianos, G., Mieli-Vergani, G., Tanner, S., Sternlieb, I., Schilsky, M., Cox, D., & Berr, F. (2003). Diagnosis and phenotypic classification of Wilson disease. Liver International, 23, 139–142.

    PubMed  Google Scholar 

  20. Ferenci, P., Stremmel, W., Czlonkowska, A., Szalay, F., Viveiros, A., Stattermayer, A. F., Bruha, R., Houwen, R., Pop, T., Stauber, R., Gschwantler, M., Pfeiffenberger, J., Yurdaydin, C., Aigner, E., Steindl-Munda, P., Dienes, H. P., Zoller, H., & Weiss, K. H. (2018) Age, sex, but not ATP7B genotype effectively influences the clinical phenotype of Wilson disease. Hepatology. https://doi.org/10.1002/hep.30280.

    Article  PubMed  Google Scholar 

  21. Gall, W. E., Beebe, K., Lawton, K. A., Adam, K. P., Mitchell, M. W., Nakhle, P. J., Ryals, J. A., Milburn, M. V., Nannipieri, M., Camastra, S., Natali, A., Ferrannini, E., & RISC Study Group. (2010). alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE, 5, e10883.

    PubMed  PubMed Central  Google Scholar 

  22. Gao, X., Chen, W., Li, R., Wang, M., Chen, C., Zeng, R., & Deng, Y. (2012). Systematic variations associated with renal disease uncovered by parallel metabolomics of urine and serum. BMC Systems Biology, 6(Suppl 1), S14.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gasser, T., Moyer, J. D., & Handschumacher, R. E. (1981). Novel single-pass exchange of circulating uridine in rat liver. Science, 213, 777–778.

    CAS  PubMed  Google Scholar 

  24. Gaynes, B. I., & Watkins, J. B. III (1989). Comparison of glucose, sorbitol and fructose accumulation in lens and liver of diabetic and insulin-treated rats and mice. Comparative Biochemistry and Physiology, Part B, 92, 685–690.

    CAS  Google Scholar 

  25. Huster, D., Kuhne, A., Bhattacharjee, A., Raines, L., Jantsch, V., Noe, J., Schirrmeister, W., Sommerer, I., Sabri, O., Berr, F., Mossner, J., Stieger, B., Caca, K., & Lutsenko, S. (2012). Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology, 142, 947–956 e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kalita, J., Kumar, V., Misra, U. K., Ranjan, A., Khan, H., & Konwar, R. (2014). A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. Journal of Neuroimmunology, 274, 141–148.

    CAS  PubMed  Google Scholar 

  27. Karbownik, M., Reiter, R. J., Garcia, J. J., Cabrera, J., Burkhardt, S., Osuna, C., & Lewinski, A. (2001). Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: Relevance to cancer reduction. Journal of Cell Biochemistry, 81, 507–513.

    CAS  Google Scholar 

  28. Kieffer, D. A., & Medici, V. (2017). Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence. Liver Research, 1, 121–130.

    PubMed  PubMed Central  Google Scholar 

  29. Kim, S. J., Kim, S. H., Kim, J. H., Hwang, S., & Yoo, H. J. (2016). Understanding metabolomics in biomedical research. Endocrinology and Metabolism (Seoul), 31, 7–16.

    CAS  Google Scholar 

  30. Lai, J. C., & Blass, J. P. (1984). Neurotoxic effects of copper: Inhibition of glycolysis and glycolytic enzymes. Neurochemical Research, 9, 1699–1710.

    CAS  PubMed  Google Scholar 

  31. Le, T. T., Ziemba, A., Urasaki, Y., Hayes, E., Brotman, S., & Pizzorno, G. (2013). Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation. Journal of Lipid Research, 54, 1044–1057.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee, B. H., Kim, J. M., Heo, S. H., Mun, J. H., Kim, J., Kim, J. H., Jin, H. Y., Kim, G. H., Choi, J. H., & Yoo, H. W. (2011) Proteomic analysis of the hepatic tissue of Long-Evans Cinnamon (LEC) rats according to the natural course of Wilson disease. Proteomics, 11, 3698–3705.

    CAS  PubMed  Google Scholar 

  33. Li, M., Li, Y., Chen, J., Wei, W., Pan, X., Liu, J., Liu, Q., Leu, W., Zhang, L., Yang, X., Lu, J., & Wang, K. (2007). Copper ions inhibit S-adenosylhomocysteine hydrolase by causing dissociation of NAD+ cofactor. Biochemistry, 46, 11451–11458.

    CAS  PubMed  Google Scholar 

  34. Lichtmannegger, J., Leitzinger, C., Wimmer, R., Schmitt, S., Schulz, S., Kabiri, Y., Eberhagen, C., Rieder, T., Janik, D., Neff, F., Straub, B. K., Schirmacher, P., DiSpirito, A. A., Bandow, N., Baral, B. S., Flatley, A., Kremmer, E., Denk, G., Reiter, F. P., Hohenester, S., Eckardt-Schupp, F., Dencher, N. A., Adamski, J., Sauer, V., Niemietz, C., Schmidt, H. H., Merle, U., Gotthardt, D. N., Kroemer, G., Weiss, K. H., & Zischka, H. (2016). Methanobactin reverses acute liver failure in a rat model of Wilson disease. Journal of Clinical Investigation, 126, 2721–2735.

    PubMed  Google Scholar 

  35. Macomber, L., & Imlay, J. A. (2009). The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proceedings of National Academy of Sciences of United States of America, 106, 8344–8349.

    CAS  Google Scholar 

  36. Mandal, N., Bhattacharjee, D., Rout, J. K., Dasgupta, A., Bhattacharya, G., Sarkar, C., & Gangopadhyaya, P. K. (2016). Effect of copper on l-cysteine/l-cystine influx in normal human erythrocytes and erythrocytes of Wilson’s disease. Indian Journal of Clinical Biochemistry, 31, 468–472.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Maus, A., & Peters, G. J. (2017). Glutamate and alpha-ketoglutarate: Key players in glioma metabolism. Amino Acids, 49, 21–32.

    CAS  PubMed  Google Scholar 

  38. Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., & Schnabl, B. (2015). Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB Journal, 29, 1043–1055.

    CAS  PubMed  Google Scholar 

  39. Medici, V., Kieffer, D. A., Shibata, N. M., Chima, H., Kim, K., Canovas, A., Medrano, J. F., Islas-Trejo, A. D., Kharbanda, K. K., Olson, K., Su, R. J., Islam, M. S., Syed, R., Keen, C. L., Miller, A. Y., Rutledge, J. C., Halsted, C. H., & LaSalle, J. M. (2016) Wilson disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model. Epigenetics, 11, 804–818.

    PubMed  PubMed Central  Google Scholar 

  40. Medici, V., Shibata, N. M., Kharbanda, K. K., Islam, M. S., Keen, C. L., Kim, K., Tillman, B., French, S. W., Halsted, C. H., & LaSalle, J. M. (2014) Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics, 9, 286–296.

    CAS  PubMed  Google Scholar 

  41. Medici, V., Shibata, N. M., Kharbanda, K. K., LaSalle, J. M., Woods, R., Liu, S., Engelberg, J. A., Devaraj, S., Torok, N. J., Jiang, J. X., Havel, P. J., Lonnerdal, B., Kim, K., & Halsted, C. H. (2013) Wilson’s disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology, 57, 555–565.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Metges, C. C. (2000). Contribution of microbial amino acids to amino acid homeostasis of the host. The Journal of Nutrition, 130, 1857S–1864S.

    CAS  PubMed  Google Scholar 

  43. Nagasaka, H., Inoue, I., Inui, A., Komatsu, H., Sogo, T., Murayama, K., Murakami, T., Yorifuji, T., Asayama, K., Katayama, S., Uemoto, S., Kobayashi, K., Takayanagi, M., Fujisawa, T., & Tsukahara, H. (2006). Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: Hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress. Pediatric Research, 60, 472–477.

    CAS  PubMed  Google Scholar 

  44. Naik, S. R., & Kokil, G. R. (2013) Development and discovery avenues in bioactive natural products for glycemic novel therapeutics. In Atta-ur-Rahman (Ed.), Studies in natural products chemistry (pp. 431–466). Amsterdam: Elsevier.

  45. Nussinson, E., Shahbari, A., Shibli, F., Chervinsky, E., Trougouboff, P., & Markel, A. (2013). Diagnostic challenges of Wilson’s disease presenting as acute pancreatitis, cholangitis, and jaundice. World Journal of Hepatology, 5, 649–653.

    PubMed  PubMed Central  Google Scholar 

  46. Obrosova, I. G. (2005). Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxidants & Redox Signaling, 7, 1543–1552.

    CAS  Google Scholar 

  47. Ogihara, H., Ogihara, T., Miki, M., Yasuda, H., & Mino, M. (1995). Plasma copper and antioxidant status in Wilson’s disease. Pediatric Research, 37, 219–226.

    CAS  PubMed  Google Scholar 

  48. Park, J. Y., Mun, J. H., Lee, B. H., Heo, S. H., Kim, G. H., & Yoo, H. W. (2009). Proteomic analysis of sera of asymptomatic, early-stage patients with Wilson’s disease. Proteomics Clinical Applications, 3, 1185–1190.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pierson, H., Muchenditsi, A., Kim, B.-E., Ralle, M., Zachos, N., Huster, D., & Lutsenko, S. (2018). The function of ATPase copper transporter ATP7B in intestine. Gastroenterology, 154, 168–180.e5.

    CAS  PubMed  Google Scholar 

  50. Poulsom, R., & Heath, H. (1983). Inhibition of aldose reductase in five tissues of the streptozotocin-diabetic rat. Biochemical Pharmacology, 32, 1495–1499.

    CAS  PubMed  Google Scholar 

  51. Robbins, K. R., & Baker, D. H. (1980). Effect of high-level copper feeding on the sulfur amino acid need of chicks fed corn-soybean meal and purified crystalline amino acid diets. Poultry Science, 59, 1099–1108.

    CAS  PubMed  Google Scholar 

  52. Roberts, E. A., & Schilsky, M. L. and American Association for Study of Liver, D. (2008) Diagnosis and treatment of Wilson disease: An update. Hepatology 47, 2089–2111.

    CAS  PubMed  Google Scholar 

  53. Rocha, A. G., & Dancis, A. (2016). Life without Fe–S clusters. Molecular Microbiology, 99, 821–826.

    CAS  PubMed  Google Scholar 

  54. Roelofsen, H., Balgobind, R., & Vonk, R. J. (2004). Proteomic analyzes of copper metabolism in an in vitro model of Wilson disease using surface enhanced laser desorption/ionization-time of flight-mass spectrometry. Journal of Cell Biochemistry, 93, 732–740.

    CAS  Google Scholar 

  55. Rossi, L., Lombardo, M. F., Ciriolo, M. R., & Rotilio, G. (2004). Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochemical Research, 29, 493–504.

    CAS  PubMed  Google Scholar 

  56. Rouault, T. A. (2012). Biogenesis of iron-sulfur clusters in mammalian cells: New insights and relevance to human disease. Disease Models & Mechanisms, 5, 155–164.

    CAS  Google Scholar 

  57. Sheline, C. T., & Choi, D. W. (2004). Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. Annals of Neurology, 55, 645–653.

    CAS  PubMed  Google Scholar 

  58. Simpson, D. M., Beynon, R. J., Robertson, D. H., Loughran, M. J., & Haywood, S. (2004). Copper-associated liver disease: A proteomics study of copper challenge in a sheep model. Proteomics, 4, 524–536.

    CAS  PubMed  Google Scholar 

  59. Sipos, K., Lange, H., Fekete, Z., Ullmann, P., Lill, R., & Kispal, G. (2002). Maturation of cytosolic iron-sulfur proteins requires glutathione. Journal of Biological Chemistry, 277, 26944–26949.

    CAS  PubMed  Google Scholar 

  60. Song, M., Li, X., Zhang, X., Shi, H., Vos, M. B., Wei, X., Wang, Y., Gao, H., Rouchka, E. C., Yin, X., Zhou, Z., Prough, R. A., Cave, M. C., & McClain, C. J. (2018). Dietary copper–fructose interactions alter gut microbial activity in male rats. American Journal of Physiology-Gastrointestinal and Liver Physiology, 314, G119–G130.

    PubMed  Google Scholar 

  61. Summer, K. H., & Eisenburg, J. (1985). Low content of hepatic reduced glutathione in patients with Wilson’s disease. Biochemical Medicine, 34, 107–111.

    CAS  PubMed  Google Scholar 

  62. Thomas, M., & Hughes, R. E. (1983). A relationship between ascorbic acid and threonic acid in guinea-pigs. Food and Chemical Toxicology, 21, 449–452.

    CAS  PubMed  Google Scholar 

  63. Umeki, S., Ohga, R., Konishi, Y., Yasuda, T., Morimoto, K., & Terao, A. (1986). Oral zinc therapy normalizes serum uric acid level in Wilson’s disease patients. American Journal of Medical Sciences, 292, 289–292.

    CAS  Google Scholar 

  64. Vallieres, C., Holland, S. L., & Avery, S. V. (2017). Mitochondrial ferredoxin determines vulnerability of cells to copper excess. Cell Chemical Biology, 24, 1228–1237.e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Vernis, L., El Banna, N., Baille, D., Hatem, E., Heneman, A., & Huang, M. E. (2017) Fe–S clusters emerging as targets of therapeutic drugs. Oxidative Medicine and Cellular Longevity, 2017, 3647657.

    PubMed  PubMed Central  Google Scholar 

  66. Wang, H., Zhou, Z., Hu, J., Han, Y., Wang, X., Cheng, N., Wu, Y., & Yang, R. (2015). Renal impairment in different phenotypes of Wilson disease. Neurological Sciences, 36, 2111–2115.

    PubMed  Google Scholar 

  67. Wang, J. B., Pu, S. B., Sun, Y., Li, Z. F., Niu, M., Yan, X. Z., Zhao, Y. L., Wang, L. F., Qin, X. M., Ma, Z. J., Zhang, Y. M., Li, B. S., Luo, S. Q., Gong, M., Sun, Y. Q., Zou, Z. S., & Xiao, X. H. (2014) Metabolomic profiling of autoimmune hepatitis: The diagnostic utility of nuclear magnetic resonance spectroscopy. Journal of Proteome Research, 13(8), 3792–3801.

    CAS  PubMed  Google Scholar 

  68. Whyte, I. M., Francis, B., & Dawson, A. H. (2007). Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: Analysis of the Hunter Area Toxicology Service (HATS) database. Current Medical Research and Opinion, 23, 2359–2368.

    CAS  PubMed  Google Scholar 

  69. Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C., & Siuzdak, G. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of National Academy of Sciences of United States of America, 106, 3698–3703.

    CAS  Google Scholar 

  70. Wilmarth, P. A., Short, K. K., Fiehn, O., Lutsenko, S., David, L. L., & Burkhead, J. L. (2012). A systems approach implicates nuclear receptor targeting in the Atp7b(−/−) mouse model of Wilson’s disease. Metallomics, 4, 660–668.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Winquist, A., Steenland, K., & Shankar, A. (2010). Higher serum uric acid associated with decreased Parkinson’s disease prevalence in a large community-based survey. Movement Disorders, 25, 932–936.

    PubMed  Google Scholar 

  72. Xu, J., Jiang, H., Li, J., Cheng, K. K., Dong, J., & Chen, Z. (2015). 1H NMR-based metabolomics investigation of copper-laden rat: A model of Wilson’s disease. PLoS ONE, 10, e0119654.

    PubMed  PubMed Central  Google Scholar 

  73. Yisireyili, M., Takeshita, K., Saito, S., Murohara, T., & Niwa, T. (2017). Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. Nagoya Journal of Medical Science, 79, 477–486.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang, H., Yan, C., Yang, Z., Zhang, W., Niu, Y., Li, X., Qin, L., & Su, Q. (2017). Alterations of serum trace elements in patients with type 2 diabetes. Journal of Trace Elements in Medicine and Biology, 40, 91–96.

    CAS  PubMed  Google Scholar 

  75. Zheng, T., Liu, L., Shi, J., Yu, X., Xiao, W., Sun, R., Zhou, Y., Aa, J., & Wang, G. (2014). The metabolic impact of methamphetamine on the systemic metabolism of rats and potential markers of methamphetamine abuse. Molecular BioSystems, 10, 1968–1977.

    CAS  PubMed  Google Scholar 

  76. Zhou, C., Jia, H. M., Liu, Y. T., Yu, M., Chang, X., Ba, Y. M., & Zou, Z. M. (2016). Metabolism of glycerophospholipid, bile acid and retinol is correlated with the early outcomes of autoimmune hepatitis. Molecular BioSystems, 12, 1574–1585.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge Triston Mosbacher (Department of Public Health Sciences, Division of Biostatistics, University of California, Davis) for his contribution to the analysis.

Funding

This research was supported by the National Institutes of Health/NIDDK through grant number R01DK104770 (to V.M.).

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All authors took part in the study design and contributed to the final draft of the paper. In addition, VM conceived and designed the study, and wrote the paper. GS analyzed and interpreted the data, and wrote the paper. AC and TL provided the samples for the studies. NS proofread, contributed to the discussion, and assisted with arranging the final draft. KK performed the data analysis. DK managed the human subject samples and database, and contributed to data interpretation. All authors read and approved the final manuscript.

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Correspondence to Valentina Medici.

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Conflict of Interest: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors who participated in this study declared they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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Sarode, G.V., Kim, K., Kieffer, D.A. et al. Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature. Metabolomics 15, 43 (2019). https://doi.org/10.1007/s11306-019-1505-6

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Keywords

  • Copper
  • Metabolomics
  • Biomarkers
  • Phenotype