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Accurate mass and retention time library of serum lipids for type 1 diabetes research

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Abstract

Dysregulated lipid species are linked to various disease pathologies and implicated as potential biomarkers for type 1 diabetes (T1D). However, it is challenging to comprehensively profile the blood specimen lipidome with full structural details of every lipid molecule. The commonly used reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS)-based lipidomics approach is powerful for the separation of individual lipid species, but lipids belonging to different classes may still co-elute and result in ion suppression and misidentification of lipids. Using offline mixed-mode and RPLC-based two-dimensional separations coupled with MS/MS, a comprehensive lipidomic profiling was performed on human sera pooled from healthy and T1D subjects. The elution order of lipid molecular species on RPLC showed good correlations to the total number of carbons in fatty acyl chains and total number of double bonds. This observation together with fatty acyl methyl ester analysis was used to enhance the confidence of identified lipid species. The final T1D serum lipid library database contains 753 lipid molecular species with accurate mass and RPLC retention time uniquely annotated for each of the species. This comprehensive human serum lipid library can serve as a database for high-throughput RPLC-MS-based lipidomic analysis of blood samples related to T1D and other childhood diseases.

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References

  1. Wymann MP, Schneiter R. Lipid signalling in disease. Nat Rev Mol Cell Biol. 2008;9(2):162–76.

    Article  CAS  PubMed  Google Scholar 

  2. Nguyen A, Rudge SA, Zhang Q, Wakelam MJO. Using lipidomics analysis to determine signalling and metabolic changes in cells. Curr Opin Biotechnol. 2017;43:96–103.

    Article  CAS  PubMed  Google Scholar 

  3. Li X, Xu Z, Lu X, Yang X, Yin P, Kong H, et al. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry for metabonomics: biomarker discovery for diabetes mellitus. Anal Chim Acta. 2009;633(2):257–62.

    Article  CAS  PubMed  Google Scholar 

  4. Zarrouk A, Debbabi M, Bezine M, Karym EM, Badreddine A, Rouaud O, et al. Lipid biomarkers in Alzheimer’s disease. Curr Alzheimer Res. 2018;15(4):303–12.

    Article  CAS  PubMed  Google Scholar 

  5. Fox TE, Bewley MC, Unrath KA, Pedersen MM, Anderson RE, Jung DY, et al. Circulating sphingolipid biomarkers in models of type 1 diabetes. J Lipid Res. 2011;52(3):509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lamichhane S, Ahonen L, Dyrlund TS, Kemppainen E, Siljander H, Hyoty H, et al. Dynamics of plasma lipidome in progression to islet autoimmunity and type 1 diabetes—Type 1 Diabetes Prediction and Prevention Study (DIPP). Sci Rep. 2018;8(1):10635.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sorensen CM, Ding J, Zhang Q, Alquier T, Zhao R, Mueller PW, et al. Perturbations in the lipid profile of individuals with newly diagnosed type 1 diabetes mellitus: lipidomics analysis of a Diabetes Antibody Standardization Program sample subset. Clin Biochem. 2010;43(12):948–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Luppa PB, Bietenbeck A, Beaudoin C, Giannetti A. Clinically relevant analytical techniques, organizational concepts for application and future perspectives of point-of-care testing. Biotechnol Adv. 2016;34(3):139–60.

    Article  PubMed  Google Scholar 

  9. Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov. 2005;4(7):594–610.

    Article  CAS  PubMed  Google Scholar 

  10. Holcapek M, Jirasko R, Lisa M. Recent developments in liquid chromatography-mass spectrometry and related techniques. J Chromatogr A. 2012;1259:3–15.

    Article  CAS  PubMed  Google Scholar 

  11. Cajka T, Fiehn O. Increasing lipidomic coverage by selecting optimal mobile-phase modifiers in LC–MS of blood plasma. Metabolomics. 2016;12(2).

  12. Narvaez-Rivas M, Vu N, Chen GY, Zhang Q. Off-line mixed-mode liquid chromatography coupled with reversed phase high performance liquid chromatography-high resolution mass spectrometry to improve coverage in lipidomics analysis. Anal Chim Acta. 2017;954:140–50.

    Article  CAS  PubMed  Google Scholar 

  13. Narvaez-Rivas M, Zhang Q. Comprehensive untargeted lipidomic analysis using core-shell C30 particle column and high field Orbitrap mass spectrometer. J Chromatogr A. 2016;1440:123–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gao X, Zhang Q, Meng D, Isaac G, Zhao R, Fillmore TL, et al. A reversed-phase capillary ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method for comprehensive top-down/bottom-up lipid profiling. Anal Bioanal Chem. 2012;402(9):2923–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rampler E, Criscuolo A, Zeller M, El Abiead Y, Schoeny H, Hermann G, et al. A novel lipidomics workflow for improved human plasma identification and quantification using RPLC-MSn methods and isotope dilution strategies. Anal Chem. 2018;90(11):6494–501.

    Article  CAS  PubMed  Google Scholar 

  16. Wozny K, Lehmann WD, Wozny M, Akbulut BS, Brugger B. A method for the quantitative determination of glycerophospholipid regioisomers by UPLC-ESI-MS/MS. Anal Bioanal Chem. 2019;411(4):915–24.

    Article  CAS  PubMed  Google Scholar 

  17. Kind T, Liu KH, Lee DY, DeFelice B, Meissen JK, Fiehn O. LipidBlast in silico tandem mass spectrometry database for lipid identification. Nat Methods. 2013;10(8):755–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Taguchi R, Ishikawa M. Precise and global identification of phospholipid molecular species by an Orbitrap mass spectrometer and automated search engine LipidSearch. J Chromatogr A. 2010;1217(25):4229–39.

    Article  CAS  PubMed  Google Scholar 

  19. Meng D, Zhang Q, Gao X, Wu S, Lin G. LipidMiner: a software for automated identification and quantification of lipids from multiple liquid chromatography/mass spectrometry data files. Rapid Commun Mass Spectrom. 2014;28(8):981–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pluskal T, Castillo S, Villar-Briones A, Oresic M. MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinformatics. 2010;11:395.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Conrads TP, Anderson GA, Veenstra TD, Paša-Tolić L, Smith RD. Utility of accurate mass tags for proteome-wide protein identification. Anal Chem. 2000;72(14):3349–54.

    Article  CAS  PubMed  Google Scholar 

  22. Zimmer JS, Monroe ME, Qian WJ, Smith RD. Advances in proteomics data analysis and display using an accurate mass and time tag approach. Mass Spectrom Rev. 2006;25(3):450–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Creek DJ, Jankevics A, Breitling R, Watson DG, Barrett MP, Burgess KE. Toward global metabolomics analysis with hydrophilic interaction liquid chromatography-mass spectrometry: improved metabolite identification by retention time prediction. Anal Chem. 2011;83(22):8703–10.

    Article  CAS  PubMed  Google Scholar 

  24. Ding J, Sorensen CM, Jaitly N, Jiang H, Orton DJ, Monroe ME, et al. Application of the accurate mass and time tag approach in studies of the human blood lipidome. J Chromatogr B Anal Technol Biomed Life Sci. 2008;871(2):243–52.

    Article  CAS  Google Scholar 

  25. Rewers M, Bugawan TL, Norris JM, Blair A, Beaty B, Hoffman M, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia. 1996;39(7):807–12.

    Article  CAS  PubMed  Google Scholar 

  26. Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA. 2007;298(12):1420–8.

    Article  CAS  PubMed  Google Scholar 

  27. Nakanishi H, Iida Y, Shimizu T, Taguchi R. Separation and quantification of sn-1 and sn-2 fatty acid positional isomers in phosphatidylcholine by RPLC-ESIMS/MS. J Biochem. 2010;147(2):245–56.

    Article  CAS  PubMed  Google Scholar 

  28. Larsen A, Uran S, Jacobsen PB, Skotland T. Collision-induced dissociation of glycero phospholipids using electrospray ion-trap mass spectrometry. Rapid Commun Mass Spectrom. 2001;15(24):2393–8.

    Article  CAS  PubMed  Google Scholar 

  29. Hvattum E, Hagelin G, Larsen A. Study of mechanisms involved in the collision-induced dissociation of carboxylate anions from glycerophospholipids using negative ion electrospray tandem quadrupole mass spectrometry. Rapid Commun Mass Spectrom. 1998;12(19):1405–9.

    Article  CAS  PubMed  Google Scholar 

  30. Cui Z, Thomas MJ. Phospholipid profiling by tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2009;877(26):2709–15.

    Article  CAS  Google Scholar 

  31. Pi J, Wu X, Feng Y. Fragmentation patterns of five types of phospholipids by ultra-high-performance liquid chromatography electrospray ionization quadrupole time-of-flight tandem mass spectrometry. Anal Methods. 2016;8(6):1319–32.

    Article  CAS  Google Scholar 

  32. Hsu FF, Turk J. Structural characterization of unsaturated glycerophospholipids by multiple-stage linear ion-trap mass spectrometry with electrospray ionization. J Am Soc Mass Spectrom. 2008;19(11):1681–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hsu FF, Turk J. Electrospray ionization multiple-stage linear ion-trap mass spectrometry for structural elucidation of triacylglycerols: assignment of fatty acyl groups on the glycerol backbone and location of double bonds. J Am Soc Mass Spectrom. 2010;21(4):657–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hsu FF, Turk J, Thukkani AK, Messner MC, Wildsmith KR, Ford DA. Characterization of alkylacyl, alk-1-enylacyl and lyso subclasses of glycerophosphocholine by tandem quadrupole mass spectrometry with electrospray ionization. J Mass Spectrom. 2003;38(7):752–63.

    Article  CAS  PubMed  Google Scholar 

  35. Han X, Yang K, Gross RW. Multi-dimensional mass spectrometry-based shotgun lipidomics and novel strategies for lipidomic analyses. Mass Spectrom Rev. 2012;31(1):134–78.

    Article  CAS  PubMed  Google Scholar 

  36. Holčapek M, Liebisch G, Ekroos K. Lipidomic analysis. Anal Chem. 2018;90(7):4249–57.

    Article  PubMed  CAS  Google Scholar 

  37. Liebisch G, Vizcaino JA, Kofeler H, Trotzmuller M, Griffiths WJ, Schmitz G, et al. Shorthand notation for lipid structures derived from mass spectrometry. J Lipid Res. 2013;54(6):1523–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ovcacikova M, Lisa M, Cifkova E, Holcapek M. Retention behavior of lipids in reversed-phase ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr A. 2016;1450:76–85.

    Article  CAS  PubMed  Google Scholar 

  39. Nakagawa Y, Horrocks LA. Separation of alkenylacyl, alkylacyl, and diacyl analogues and their molecular species by high performance liquid chromatography. J Lipid Res. 1983;24(9):1268–75.

    CAS  PubMed  Google Scholar 

  40. Merrill AH Jr, Sullards MC, Allegood JC, Kelly S, Wang E. Sphingolipidomics: high-throughput, structure-specific, and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods. 2005;36(2):207–24.

    Article  CAS  PubMed  Google Scholar 

  41. Smith PB, Snyder AP, Harden CS. Characterization of bacterial phospholipids by electrospray ionization tandem mass spectrometry. Anal Chem. 1995;67(11):1824–30.

    Article  CAS  PubMed  Google Scholar 

  42. Han X, Gross RW. Structural determination of picomole amounts of phospholipids via electrospray ionization tandem mass spectrometry. J Am Soc Mass Spectrom. 1995;6(12):1202–10.

    Article  CAS  PubMed  Google Scholar 

  43. Bird SS, Marur VR, Sniatynski MJ, Greenberg HK, Kristal BS. Serum lipidomics profiling using LC-MS and high-energy collisional dissociation fragmentation: focus on triglyceride detection and characterization. Anal Chem. 2011;83(17):6648–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Quehenberger O, Dennis EA. The human plasma lipidome. N Engl J Med. 2011;365(19):1812–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Quehenberger O, Armando AM, Brown AH, Milne SB, Myers DS, Merrill AH, et al. Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res. 2010;51(11):3299–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou X, Mao J, Ai J, Deng Y, Roth MR, Pound C, et al. Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics. PLoS One. 2012;7(11):e48889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sandra K, Pereira Ados S, Vanhoenacker G, David F, Sandra P. Comprehensive blood plasma lipidomics by liquid chromatography/quadrupole time-of-flight mass spectrometry. J Chromatogr A. 2010;1217(25):4087–99.

    Article  CAS  PubMed  Google Scholar 

  48. Liebisch G, Binder M, Schifferer R, Langmann T, Schulz B, Schmitz G. High throughput quantification of cholesterol and cholesteryl ester by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Biochim Biophys Acta. 2006;1761(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  49. Murphy RC, Axelsen PH. Mass spectrometric analysis of long-chain lipids. Mass Spectrom Rev. 2011;30(4):579–99.

    Article  CAS  PubMed  Google Scholar 

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Funding

The work was partially supported by National Institutes of Health (NIH) grants R21 GM104678 and R01 DK114345. Clinical sample collection was supported by NIH grant R01 DK32493.

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Correspondence to Qibin Zhang.

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This research analyzed de-identified human serum samples collected from clinical studies and has IRB approval as stated in the “Materials and methods” section. All authors have read and agreed to the final version of this manuscript.

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Vu, N., Narvaez-Rivas, M., Chen, GY. et al. Accurate mass and retention time library of serum lipids for type 1 diabetes research. Anal Bioanal Chem 411, 5937–5949 (2019). https://doi.org/10.1007/s00216-019-01997-7

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  • DOI: https://doi.org/10.1007/s00216-019-01997-7

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