Proteomics in the Study of Liver Diseases

  • Lili Niu
  • Philipp E. Geyer
  • Matthias MannEmail author


In this chapter, we describe the workflow of mass spectrometry (MS)-based proteomics with a focus on shotgun proteomics. We illustrate how MS-based proteomics can be applied to study liver pathophysiology using protein expression profiling, characterization of post-translational modifications (PTMs) and protein-protein interactions (PPIs). The publications on serum or plasma proteomics in the study of liver diseases during the years 2012 to 2017 are reviewed. We analyze the proportions of studies with regard to different kinds of liver disease and different proteomics workflows applied. Remarkably, outdated proteomics techniques were still being used in recent years and even account for a large proportion of the reviewed literature. The effort spent in different liver diseases is largely skewed to hepatocellular carcinoma and hepatic viral infection while a relatively small proportion focused on non-alcoholic fatty liver disease (NAFLD), which is the most prevalent liver disease worldwide. Finally, we describe plasma proteome profiling, a novel approach for biomarker discovery studies, and how this applies to liver diseases.


Shotgun proteomics Liver disease Biomarker discovery Fibrosis Mass spectrometry Blood Plasma Serum 


  1. 1.
    Aebersold R, Mann M. Mass-spectrometric exploration of proteome structure and function. Nature. 2016;537:347–55.PubMedCrossRefGoogle Scholar
  2. 2.
    Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485–91.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Anderson NL, Ptolemy AS, Rifai N. The riddle of protein diagnostics: future bleak or bright? Clin Chem. 2013;59:194–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Azimifar SB, Nagaraj N, Cox J, Mann M. Cell-type-resolved quantitative proteomics of murine liver. Cell Metab. 2014;20:1076–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Bantscheff M, Lemeer S, Savitski MM, Kuster B. Quantitative mass spectrometry in proteomics: critical review update from 2007 to the present. Anal Bioanal Chem. 2012;404:939–65.PubMedCrossRefGoogle Scholar
  6. 6.
    Batth TS, Olsen JV. Offline high pH reversed-phase peptide fractionation for deep phosphoproteome coverage. Methods Mol Biol. 2016;1355:179–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Bekker-Jensen DB, Kelstrup CD, Batth TS, Larsen SC, Haldrup C, Bramsen JB, Sorensen KD, Hoyer S, Orntoft TF, Andersen CL, et al. An optimized shotgun strategy for the rapid generation of comprehensive human proteomes. Cell Syst. 2017;4:587–599.e584.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Blomme B, Van Steenkiste C, Callewaert N, Van Vlierberghe H. Alteration of protein glycosylation in liver diseases. J Hepatol. 2009;50:592–603.PubMedCrossRefGoogle Scholar
  9. 9.
    Bruderer R, Bernhardt OM, Gandhi T, Xuan Y, Sondermann J, Schmidt M, Gomez-Varela D, Reiter L. Optimization of experimental parameters in data-independent mass spectrometry significantly increases depth and reproducibility of results. Mol Cell Proteomics. 2017;16(12):2296–309.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Burkhart JM, Schumbrutzki C, Wortelkamp S, Sickmann A, Zahedi RP. Systematic and quantitative comparison of digest efficiency and specificity reveals the impact of trypsin quality on MS-based proteomics. J Proteome. 2012;75:1454–62.CrossRefGoogle Scholar
  11. 11.
    Catherman AD, Skinner OS, Kelleher NL. Top down proteomics: facts and perspectives. Biochem Biophys Res Commun. 2014;445:683–93.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chapple CE, Robisson B, Spinelli L, Guien C, Becker E, Brun C. Extreme multifunctional proteins identified from a human protein interaction network. Nat Commun. 2015;6:7412.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014;15:536–50.PubMedCrossRefGoogle Scholar
  14. 14.
    Colangelo CM, Chung L, Bruce C, Cheung K-H. Review of software tools for design and analysis of large scale MRM proteomic datasets. Methods. 2013;61:287–98.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Compton PD, Kelleher NL. Spinning up mass spectrometry for whole protein complexes. Nat Methods. 2012;9:1065–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics. 2014;13:2513–26.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    da Costa AN, Plymoth A, Santos-Silva D, Ortiz-Cuaran S, Camey S, Guilloreau P, Sangrajrang S, Khuhaprema T, Mendy M, Lesi OA, et al. Osteopontin and latent-TGF beta binding-protein 2 as potential diagnostic markers for HBV-related hepatocellular carcinoma. Int J Cancer. 2015;136:172–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Davies DR, Gelinas AD, Zhang C, Rohloff JC, Carter JD, O'Connell D, Waugh SM, Wolk SK, Mayfield WS, Burgin AB, et al. Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets. Proc Natl Acad Sci U S A. 2012;109:19971–6.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    de Godoy LM. SILAC yeast: from labeling to comprehensive proteome quantification. Methods Mol Biol. 2014;1156:81–109.PubMedCrossRefGoogle Scholar
  20. 20.
    de Jong L, de Koning EA, Roseboom W, Buncherd H, Wanner MJ, Dapic I, Jansen PJ, van Maarseveen JH, Corthals GL, Lewis PJ, et al. In-culture cross-linking of bacterial cells reveals large-scale dynamic protein-protein interactions at the peptide level. J Proteome Res. 2017;16:2457–71.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ding C, Li Y, Guo F, Jiang Y, Ying W, Li D, Yang D, Xia X, Liu W, Zhao Y, et al. A cell-type-resolved liver proteome. Mol Cell Proteomics. 2016;15:3190–202.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Diz AP, Truebano M, Skibinski DO. The consequences of sample pooling in proteomics: an empirical study. Electrophoresis. 2009;30:2967–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Doll S, Burlingame AL. Mass spectrometry-based detection and assignment of protein posttranslational modifications. ACS Chem Biol. 2015;10:63–71.PubMedCrossRefGoogle Scholar
  24. 24.
    Eliuk, S., and Makarov, A. (2015). Evolution of Orbitrap mass spectrometry instrumentation. Annu Rev Anal Chem 8, 61-80.PubMedCrossRefGoogle Scholar
  25. 25.
    Eng JK, McCormack AL, Yates JR. An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J Am Soc Mass Spectrom. 1994;5:976–89.PubMedCrossRefGoogle Scholar
  26. 26.
    Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM. Electrospray ionization for mass spectrometry of large biomolecules. Science. 1989;246:64–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferrin G, Ranchal I, Llamoza C, Rodriguez-Peralvarez ML, Romero-Ruiz A, Aguilar-Melero P, Lopez-Cillero P, Briceno J, Muntane J, Montero-Alvarez JL, et al. Identification of candidate biomarkers for hepatocellular carcinoma in plasma of HCV-infected cirrhotic patients by 2-D DIGE. Liver Int. 2014;34:438–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Fierro-Monti I, Racle J, Hernandez C, Waridel P, Hatzimanikatis V, Quadroni M. A novel pulse-chase SILAC strategy measures changes in protein decay and synthesis rates induced by perturbation of Proteostasis with an Hsp90 inhibitor. PLoS One. 2013;8:e80423.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fíla J, Honys D. Enrichment techniques employed in phosphoproteomics. Amino Acids. 2012;43:1025–47.PubMedCrossRefGoogle Scholar
  30. 30.
    Fujii T, Fuchs BC, Yamada S, Lauwers GY, Kulu Y, Goodwin JM, Lanuti M, Tanabe KK. Mouse model of carbon tetrachloride induced liver fibrosis: histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol. 2010;10:79.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gangadharan B, Bapat M, Rossa J, Antrobus R, Chittenden D, Kampa B, Barnes E, Klenerman P, Dwek RA, Zitzmann N. Discovery of novel biomarker candidates for liver fibrosis in hepatitis C patients: a preliminary study. PLoS One. 2012;7:e39603.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Garcia BA. What does the future hold for top down mass spectrometry? J Am Soc Mass Spectrom. 2010;21:193–202.PubMedCrossRefGoogle Scholar
  33. 33.
    Gauthier NP, Soufi B, Walkowicz WE, Pedicord VA, Mavrakis KJ, Macek B, Gin DY, Sander C, Miller ML. Cell-selective labeling using amino acid precursors for proteomic studies of multicellular environments. Nat Methods. 2013;10:768–73.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Geiger T, Cox J, Ostasiewicz P, Wisniewski JR, Mann M. Super-SILAC mix for quantitative proteomics of human tumor tissue. Nat Methods. 2010;7:383–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Geiger T, Wisniewski JR, Cox J, Zanivan S, Kruger M, Ishihama Y, Mann M. Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. Nat Protoc. 2011;6:147–57.PubMedCrossRefGoogle Scholar
  36. 36.
    Gelinas AD, Davies DR, Edwards TE, Rohloff JC, Carter JD, Zhang C, Gupta S, Ishikawa Y, Hirota M, Nakaishi Y, et al. Crystal structure of interleukin-6 in complex with a modified nucleic acid ligand. J Biol Chem. 2014;289:8720–34.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Geyer PE, Holdt LM, Teupser D, Mann M. Revisiting biomarker discovery by plasma proteomics. Mol Syst Biol. 2017;13:942.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Geyer PE, Kulak NA, Pichler G, Holdt LM, Teupser D, Mann M. Plasma proteome profiling to assess human health and disease. Cell Syst. 2016a;2:185–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Geyer PE, Wewer Albrechtsen NJ, Tyanova S, Grassl N, Iepsen EW, Lundgren J, Madsbad S, Holst JJ, Torekov SS, Mann M. Proteomics reveals the effects of sustained weight loss on the human plasma proteome. Mol Syst Biol. 2016b;12:901.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Gilar M, Olivova P, Daly AE, Gebler JC. Orthogonality of separation in two-dimensional liquid chromatography. Anal Chem. 2005;77:6426–34.PubMedCrossRefGoogle Scholar
  41. 41.
    Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver development. Development. 2015;142:2094–108.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Greten TF, Papendorf F, Bleck JS, Kirchhoff T, Wohlberedt T, Kubicka S, Klempnauer J, Galanski M, Manns MP. Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. Br J Cancer. 2005;92:1862–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O, et al. A protein complex network of Drosophila melanogaster. Cell. 2011;147:690–703.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Han J, Zhang M, Froese S, Dai FF, Robitaille M, Bhattacharjee A, Huang X, Jia W, Angers S, Wheeler MB, et al. The identification of novel protein-protein interactions in liver that affect glucagon receptor activity. PLoS One. 2015;10:e0129226.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hanke S, Besir H, Oesterhelt D, Mann M. Absolute SILAC for accurate quantitation of proteins in complex mixtures down to the attomole level. J Proteome Res. 2008;7:1118–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Hartwig S, Czibere A, Kotzka J, Passlack W, Haas R, Eckel J, Lehr S. Combinatorial hexapeptide ligand libraries (ProteoMiner): an innovative fractionation tool for differential quantitative clinical proteomics. Arch Physiol Biochem. 2009;115:155–60.PubMedCrossRefGoogle Scholar
  47. 47.
    He X, Hong Y, Wang X, Zhang X, Long J, Li H, Zhang B, Chen S, Liu Q, Li H, et al. Identification and clinical significance of an elevated level of serum aminoacylase-1 autoantibody in patients with hepatitis B virus-related liver cirrhosis. Mol Med Rep. 2016;14:4255–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, Gak IA, Weisswange I, Mansfeld J, Buchholz F, et al. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell. 2015;163:712–23.PubMedCrossRefGoogle Scholar
  49. 49.
    Hendriks IA, Lyon D, Young C, Jensen LJ, Vertegaal AC, Nielsen ML. Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat Struct Mol Biol. 2017;24:325–36.PubMedCrossRefGoogle Scholar
  50. 50.
    Hensley P. SOMAmers and SOMAscan – a protein biomarker discovery platform for rapid analysis of sample collections from bench top to the clinic. J Biomol Tech. 2013;24:S5.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Hernandez B, Parnell A, Pennington SR. Why have so few proteomic biomarkers “survived” validation? (sample size and independent validation considerations). Proteomics. 2014;14:1587–92.PubMedCrossRefGoogle Scholar
  52. 52.
    Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K, et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature. 2002;415:180–3.PubMedCrossRefGoogle Scholar
  53. 53.
    Huang Y, Zhu H. Protein array-based approaches for biomarker discovery in cancer. Genomics Proteomics Bioinformatics. 2017;15:73–81.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Humphrey SJ, Azimifar SB, Mann M. High-throughput phosphoproteomics reveals in vivo insulin signaling dynamics. Nat Biotechnol. 2015;33:990–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, Colby G, Gebreab F, Gygi MP, Parzen H, et al. Architecture of the human interactome defines protein communities and disease networks. Nature. 2017;545:505–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Jadot M, Boonen M, Thirion J, Wang N, Xing J, Zhao C, Tannous A, Qian M, Zheng H, Everett JK, et al. Accounting for protein subcellular localization: a compartmental map of the rat liver proteome. Mol Cell Proteomics. 2017;16(2):194–212.PubMedCrossRefGoogle Scholar
  57. 57.
    Jiang Z-H, Chen Q-Y, Harrison TJ, Li G-J, Wang X-Y, Li H, Hu L-P, Li K-W, Yang Q-L, Tan C, et al. Hepatitis B virus Core promoter double mutations (A1762T, G1764A) are associated with lower levels of serum dihydrolipoyl dehydrogenase. Intervirology. 2016;59:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kaiser SE, Riley BE, Shaler TA, Trevino RS, Becker CH, Schulman H, Kopito RR. Protein standard absolute quantification (PSAQ) method for the measurement of cellular ubiquitin pools. Nat Methods. 2011;8:691–6.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kampf C, Mardinoglu A, Fagerberg L, Hallstrom BM, Edlund K, Lundberg E, Ponten F, Nielsen J, Uhlen M. The human liver-specific proteome defined by transcriptomics and antibody-based profiling. FASEB J. 2014;28:2901–14.PubMedCrossRefGoogle Scholar
  60. 60.
    Karas M, Hillenkamp F. Laser desorption ionization of proteins with molecular masses exceeding 10,000 daltons. Anal Chem. 1988;60:2299–301.PubMedCrossRefGoogle Scholar
  61. 61.
    Karpievitch YV, Polpitiya AD, Anderson GA, Smith RD, Dabney AR. Liquid chromatography mass spectrometry-based proteomics: biological and technological aspects. Ann Appl Stat. 2010;4:1797–823.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kirkwood KJ, Ahmad Y, Larance M, Lamond AI. Characterization of native protein complexes and protein isoform variation using size-fractionation-based quantitative proteomics. Mol Cell Proteomics. 2013;12:3851–73.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Krogan NJ, Cagney G, Yu H, Zhong G, Guo X, Ignatchenko A, Li J, Pu S, Datta N, Tikuisis AP, et al. Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature. 2006;440:637–43.PubMedCrossRefGoogle Scholar
  64. 64.
    Krüger M, Moser M, Ussar S, Thievessen I, Luber CA, Forner F, Schmidt S, Zanivan S, Fässler R, Mann M. SILAC mouse for quantitative proteomics uncovers Kindlin-3 as an essential factor for red blood cell function. Cell. 2008;134:353–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Kuakarn S, SomParn P, Tangkijvanich P, Mahachai V, Thongboonkerd V, Hirankarn N. Serum proteins in chronic hepatitis B patients treated with peginterferon alfa-2b. World J Gastroenterol. 2013;19:5067–75.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kulak NA, Geyer PE, Mann M. Loss-less nano-fractionator for high sensitivity, high coverage proteomics. Mol Cell Proteomics. 2017;16:694–705.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kulak NA, Pichler G, Paron I, Nagaraj N, Mann M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat Methods. 2014;11:319–24.PubMedCrossRefGoogle Scholar
  68. 68.
    Lai KK, Kolippakkam D, Beretta L. Comprehensive and quantitative proteome profiling of the mouse liver and plasma. Hepatology. 2008;47:1043–51.PubMedCrossRefGoogle Scholar
  69. 69.
    Larance M, Bailly AP, Pourkarimi E, Hay RT, Buchanan G, Coulthurst S, Xirodimas DP, Gartner A, Lamond AI. Stable isotope labeling with amino acids in nematodes. Nat Methods. 2011;8:849–51.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lee HJ, Cha HJ, Lim JS, Lee SH, Song SY, Kim H, Hancock WS, Yoo JS, Paik YK. Abundance-ratio-based semiquantitative analysis of site-specific N-linked glycopeptides present in the plasma of hepatocellular carcinoma patients. J Proteome Res. 2014a;13:2328–38.PubMedCrossRefGoogle Scholar
  71. 71.
    Lee JY, Kim JY, Cheon MH, Park GW, Ahn YH, Moon MH, Yoo JS. MRM validation of targeted nonglycosylated peptides from N-glycoprotein biomarkers using direct trypsin digestion of undepleted human plasma. J Proteome. 2014b;98:206–17.CrossRefGoogle Scholar
  72. 72.
    Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011;25:195–206.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Liko I, Allison TM, Hopper JTS, Robinson CV. Mass spectrometry guided structural biology. Curr Opin Struct Biol. 2016;40:136–44.PubMedCrossRefGoogle Scholar
  74. 74.
    Liu CC, Wang YH, Chuang EY, Tsai MH, Chuang YH, Lin CL, Liu CJ, Hsiao BY, Lin SM, Liu LY, et al. Identification of a liver cirrhosis signature in plasma for predicting hepatocellular carcinoma risk in a population-based cohort of hepatitis B carriers. Mol Carcinog. 2014;53:58–66.PubMedCrossRefGoogle Scholar
  75. 75.
    Liu F, Rijkers DTS, Post H, Heck AJR. Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nat Methods. 2015;12:1179–84.PubMedCrossRefGoogle Scholar
  76. 76.
    Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P, Dooley S. Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol. 2013;304:G449–68.PubMedCrossRefGoogle Scholar
  77. 77.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lu P, Vogel C, Wang R, Yao X, Marcotte EM. Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol. 2007;25:117–24.PubMedCrossRefGoogle Scholar
  79. 79.
    Lundby A, Lage K, Weinert BT, Bekker-Jensen DB, Secher A, Skovgaard T, Kelstrup CD, Dmytriyev A, Choudhary C, Lundby C, et al. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2012;2:419–31.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Mann M, Hojrup P, Roepstorff P. Use of mass spectrometric molecular weight information to identify proteins in sequence databases. Biol Mass Spectrom. 1993;22:338–45.PubMedCrossRefGoogle Scholar
  81. 81.
    Mann M, Wilm M. Error-tolerant identification of peptides in sequence databases by peptide sequence tags. Anal Chem. 1994;66:4390–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Manns MP. Liver cirrhosis, transplantation and organ shortage. Dtsch Arztebl Int. 2013;110:83–4.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Marfa S, Crespo G, Reichenbach V, Forns X, Casals G, Morales-Ruiz M, Navasa M, Jimenez W. Lack of a 5.9 kDa peptide C-terminal fragment of fibrinogen alpha chain precedes fibrosis progression in patients with liver disease. PLoS One. 2014;9:e109254.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Matthes A, Kohl K, Schulze WX. SILAC and alternatives in studying cellular proteomes of plants. Methods Mol Biol. 2014;1188:65–83.PubMedCrossRefGoogle Scholar
  85. 85.
    McAnena P, Brown JAL, Kerin MJ. Circulating nucleosomes and nucleosome modifications as biomarkers in cancer. Cancer. 2017;9:5.CrossRefGoogle Scholar
  86. 86.
    Miller MH, Walsh SV, Atrih A, Huang JT, Ferguson MA, Dillon JF. Serum proteome of nonalcoholic fatty liver disease: a multimodal approach to discovery of biomarkers of nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2014;29:1839–47.PubMedCrossRefGoogle Scholar
  87. 87.
    Navare AT, Chavez JD, Zheng C, Weisbrod CR, Eng JK, Siehnel R, Singh PK, Manoil C, Bruce JE. Probing the protein interaction network of Pseudomonas aeruginosa cells by chemical cross-linking mass spectrometry. Structure. 2015;23:762–73.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ong SE, Mann M. A practical recipe for stable isotope labeling by amino acids in cell culture (SILAC). Nat Protoc. 2006;1:2650–60.PubMedCrossRefGoogle Scholar
  89. 89.
    Ori A, Toyama BH, Harris MS, Bock T, Iskar M, Bork P, Ingolia NT, Hetzer MW, Beck M. Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats. Cell Syst. 2015;1:224–37.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Ow SY, Salim M, Noirel J, Evans C, Wright PC. Minimising iTRAQ ratio compression through understanding LC-MS elution dependence and high-resolution HILIC fractionation. Proteomics. 2011;11:2341–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Paek J, Kalocsay M, Staus DP, Wingler L, Pascolutti R, Paulo JA, Gygi SP, Kruse AC. Multidimensional tracking of GPCR signaling via peroxidase-catalyzed proximity labeling. Cell. 2017;169:338–349.e311.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Pagel O, Loroch S, Sickmann A, Zahedi RP. Current strategies and findings in clinically relevant post-translational modification-specific proteomics. Expert Rev Proteomics. 2015;12:235–53.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Pappin DJ, Hojrup P, Bleasby AJ. Rapid identification of proteins by peptide-mass fingerprinting. Curr Biol. 1993;3:327–32.PubMedCrossRefGoogle Scholar
  94. 94.
    Peterson AC, Russell JD, Bailey DJ, Westphall MS, Coon JJ. Parallel reaction monitoring for high resolution and high mass accuracy quantitative, targeted proteomics. Mol Cell Proteomics. 2012;11:1475–88.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Peveling-Oberhag J, Seiz A, Döring C, Hartmann S, Köberle V, Liese J, Zeuzem S, Hansmann M-L, Piiper A. MicroRNA profiling of laser-microdissected hepatocellular carcinoma reveals an oncogenic phenotype of the tumor capsule. Transl Oncol. 2014;7:672–80.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Picotti P, Aebersold R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat Methods. 2012;9:555–66.PubMedCrossRefGoogle Scholar
  97. 97.
    Poon TC, Chan HL, Leung HW, Lo A, Lau RH, Hui AY, Sung JJ. Liver cirrhosis-specific glycoforms of serum proteins in chronic hepatitis B infection: identification by lectin affinity chromatography and quantitative proteomic profiling. Hong Kong Med J. 2015;21 Suppl 4:22–6.PubMedGoogle Scholar
  98. 98.
    Powell K. New platform for cataloging hundreds of proteins gets test drive. Nat Med. 2014;20:1082–3.PubMedCrossRefGoogle Scholar
  99. 99.
    Rajski, Ł., Gómez-Ramos, M.D.M., And Fernández-Alba, A.R. (2014). Large pesticide multiresidue screening method by liquid chromatography-Orbitrap mass spectrometry in full scan mode applied to fruit and vegetables. J Chromatogr A 1360, 119–127.PubMedCrossRefGoogle Scholar
  100. 100.
    Rath T, Hage L, Kugler M, Menendez Menendez K, Zachoval R, Naehrlich L, Schulz R, Roderfeld M, Roeb E. Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease. PLoS One. 2013;8:e58955.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Rauniyar N, Yates JR. Isobaric Labeling-based relative quantification in shotgun proteomics. J Proteome Res. 2014;13:5293–309.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Rhee H-W, Zou P, Udeshi ND, Martell JD, Mootha VK, Carr SA, Ting AY. Proteomic mapping of mitochondria in living cells via spatially-restricted enzymatic tagging. Science. 2013;339:1328–31.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Rifai N, Gillette MA, Carr SA. Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol. 2006;24:971–83.PubMedCrossRefGoogle Scholar
  104. 104.
    Robles MS, Humphrey SJ, Mann M. Phosphorylation is a central mechanism for circadian control of metabolism and physiology. Cell Metab. 2017;25:118–27.PubMedCrossRefGoogle Scholar
  105. 105.
    Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S, Khainovski N, Pillai S, Dey S, Daniels S, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics. 2004;3:1154–69.PubMedCrossRefGoogle Scholar
  106. 106.
    Sacco F, Humphrey SJ, Cox J, Mischnik M, Schulte A, Klabunde T, Schäfer M, Mann M. Glucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion. Nat Commun. 2016;7:13250.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Safaei A, Rezaei Tavirani M, Arefi Oskouei A, Zamanian Azodi M, Mohebbi SR, Nikzamir AR. Protein-protein interaction network analysis of cirrhosis liver disease. Gastroenterol Hepatol Bed Bench. 2016;9:114–23.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Savitski MM, Mathieson T, Zinn N, Sweetman G, Doce C, Becher I, Pachl F, Kuster B, Bantscheff M. Measuring and managing ratio compression for accurate iTRAQ/TMT quantification. J Proteome Res. 2013;12:3586–98.PubMedCrossRefGoogle Scholar
  109. 109.
    Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M. Global quantification of mammalian gene expression control. Nature. 2011;473:337–42.PubMedCrossRefGoogle Scholar
  110. 110.
    Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology. 2012;55:483–90.PubMedCrossRefGoogle Scholar
  111. 111.
    Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, Kongi K, Cantuti L, Hanisch U-K, Philips M-A, et al. Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci. 2015;18:1819–31.PubMedCrossRefGoogle Scholar
  112. 112.
    Singhal N, Kumar M, Kanaujia PK, Virdi JS. MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis. Front Microbiol. 2015;6:791.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Skates SJ, Gillette MA, LaBaer J, Carr SA, Anderson L, Liebler DC, Ransohoff D, Rifai N, Kondratovich M, Tezak Z, et al. Statistical design for biospecimen cohort size in proteomics-based biomarker discovery and verification studies. J Proteome Res. 2013;12:5383–94.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Sun A, Jiang Y, Wang X, Liu Q, Zhong F, He Q, Guan W, Li H, Sun Y, Shi L, et al. Liverbase: a comprehensive view of human liver biology. J Proteome Res. 2010;9:50–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Sury MD, Chen J-X, Selbach M. The SILAC fly allows for accurate protein quantification in vivo. Mol Cell Proteomics. 2010;9:2173–83.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Thaysen-Andersen M, Packer NH, Schulz BL. Maturing glycoproteomics technologies provide unique structural insights into the N-glycoproteome and its regulation in health and disease. Mol Cell Proteomics. 2016;15:1773–90.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Thompson A, Schafer J, Kuhn K, Kienle S, Schwarz J, Schmidt G, Neumann T, Johnstone R, Mohammed AK, Hamon C. Tandem mass tags: a novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal Chem. 2003;75:1895–904.PubMedCrossRefGoogle Scholar
  118. 118.
    Ting L, Rad R, Gygi SP, Haas W. MS3 eliminates ratio distortion in isobaric labeling-based multiplexed quantitative proteomics. Nat Methods. 2011;8:937–40.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Tyanova S, Mann M, Cox J. MaxQuant for in-depth analysis of large SILAC datasets. Methods Mol Biol. 2014;1188:351–64.PubMedCrossRefGoogle Scholar
  120. 120.
    Udeshi ND, Mertins P, Svinkina T, Carr SA. Large-scale identification of ubiquitination sites by mass spectrometry. Nat Protoc. 2013;8:1950–60.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Wang WW, Ang SF, Kumar R, Heah C, Utama A, Tania NP, Li H, Tan SH, Poo D, Choo SP, et al. Identification of serum monocyte chemoattractant protein-1 and prolactin as potential tumor markers in hepatocellular carcinoma. PLoS One. 2013;8:e68904.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Wang Y, Yang F, Gritsenko MA, Wang Y, Clauss T, Liu T, Shen Y, Monroe ME, Lopez-Ferrer D, Reno T, et al. Reversed-phase chromatography with multiple fraction concatenation strategy for proteome profiling of human MCF10A cells. Proteomics. 2011;11:2019–26.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Wilm M. Principles of electrospray ionization. Mol Cell Proteomics. 2011;10:M111.009407.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wisniewski JR, Hein MY, Cox J, Mann M. A “proteomic ruler” for protein copy number and concentration estimation without spike-in standards. Mol Cell Proteomics. 2014;13:3497–506.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Wiśniewski JR, Ostasiewicz P, Duś K, Zielińska DF, Gnad F, Mann M. Extensive quantitative remodeling of the proteome between normal colon tissue and adenocarcinoma. Mol Syst Biol. 2012;8:611.Google Scholar
  126. 126.
    Wongtrakul J, Thongtan T, Roytrakul S, Kumrapich B, Janphen K, Praparattanapan J, Supparatpinyo K, Smith DR. Proteomic analysis of serum and urine of HIV-monoinfected and HIV/HCV-coinfected patients undergoing long term treatment with nevirapine. Dis Markers. 2014;2014:315824.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Yang J, Yang L, Li B, Zhou W, Zhong S, Zhuang Z, Yang B, Chen M, Feng Q. iTRAQ-based proteomics identification of serum biomarkers of two chronic hepatitis B subtypes diagnosed by traditional Chinese medicine. Biomed Res Int. 2016;2016:3290260.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Yates JR 3rd, Speicher S, Griffin PR, Hunkapiller T. Peptide mass maps: a highly informative approach to protein identification. Anal Biochem. 1993;214:397–408.PubMedCrossRefGoogle Scholar
  129. 129.
    Yu C, Xu C, Xu L, Yu J, Miao M, Li Y. Serum proteomic analysis revealed diagnostic value of hemoglobin for nonalcoholic fatty liver disease. J Hepatol. 2012;56:241–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Zeiler M, Straube WL, Lundberg E, Uhlen M, Mann M. A protein epitope signature tag (PrEST) library allows SILAC-based absolute quantification and multiplexed determination of protein copy numbers in cell lines. Mol Cell Proteomics. 2012;11:O111.009613.PubMedCrossRefGoogle Scholar
  131. 131.
    Zhang G, Fenyo D, Neubert TA. Evaluation of the variation in sample preparation for comparative proteomics using stable isotope labeling by amino acids in cell culture. J Proteome Res. 2009;8:1285–92.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Zhang Y, Fonslow BR, Shan B, Baek M-C, Yates JR. Protein analysis by shotgun/bottom-up proteomics. Chem Rev. 2013;113:2343–94.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Zhang Y, Zhu J, Yin H, Marrero J, Zhang XX, Lubman DM. ESI-LC-MS method for haptoglobin fucosylation analysis in hepatocellular carcinoma and liver cirrhosis. J Proteome Res. 2015;14:5388–95.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, et al. Regulation of cellular metabolism by protein lysine acetylation. Science. 2010;327:1000–4.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Zhou C, Simpson KL, Lancashire LJ, Walker MJ, Dawson MJ, Unwin RD, Rembielak A, Price P, West C, Dive C, et al. Statistical considerations of optimal study design for human plasma proteomics and biomarker discovery. J Proteome Res. 2012;11:2103–13.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Zhou M, Lucas DA, Chan KC, Issaq HJ, Petricoin EF 3rd, Liotta LA, Veenstra TD, Conrads TP. An investigation into the human serum “interactome”. Electrophoresis. 2004;25:1289–98.PubMedCrossRefGoogle Scholar
  137. 137.
    Zhou Y, Deng X, Zang N, Li H, Li G, Li C, He M. Transcriptomic and proteomic investigation of HSP90A as a potential biomarker for HCC. Med Sci Monit. 2015;21:4039–49.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Zhu J, Sun Z, Cheng K, Chen R, Ye M, Xu B, Sun D, Wang L, Liu J, Wang F, et al. Comprehensive mapping of protein N-glycosylation in human liver by combining hydrophilic interaction chromatography and hydrazide chemistry. J Proteome Res. 2014;13:1713–21.PubMedCrossRefGoogle Scholar
  139. 139.
    Zhu J, Wu J, Yin H, Marrero J, Lubman DM. Mass spectrometric N-glycan analysis of haptoglobin from patient serum samples using a 96-well plate format. J Proteome Res. 2015;14:4932–9.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Zielinska DF, Gnad F, Wiśniewski JR, Mann M. Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints. Cell. 2010;141:897–907.PubMedCrossRefGoogle Scholar
  141. 141.
    Qian W-J, Kaleta DT, Petritis BO, Jiang H, Liu T, Zhang X, Mottaz HM, Varnum SM, Camp DG, Huang L, Fang X, Zhang W-W, Smith RD. Enhanced detection of low abundance human plasma proteins using a Tandem IgY12-Supermix immunoaffinity separation strategy. Mol Cell Proteomics. 2008;7(10):1963–73.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Winter SV, Meier F, Wichmann C, Cox J, Mann M, Meissner F. EASI-tag enables accurate multiplexed and interference-free MS2-based proteome quantification. Nat Methods. 2018;15(7):527–30.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Novo Nordisk Foundation Center for Protein Research, Faculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany

Personalised recommendations