Journal of Inherited Metabolic Disease

, Volume 34, Issue 3, pp 583–592 | Cite as

On the future of “omics”: lipidomics

  • William J. Griffiths
  • Michael Ogundare
  • Christopher M. Williams
  • Yuqin Wang
SSIEM Symposium 2010



Following in the wake of the genomic and proteomic revolutions new fields of “omics” research are emerging. The metabolome provides the natural complement to the genome and proteome, however, the extreme physicochemical diversity of the metabolome leads to a subdivision of metabolites into compounds soluble in aqueous solutions or those soluble in organic solvents. A complete molecular and quantitative investigation of the latter when isolated from tissue, fluid or cells constitutes lipidomics. Like proteomics, lipidomics is a subject which is both technology driven and technology driving, with the primary technologies being mass spectrometry, with or without on-line chromatography and computer-assisted data analysis. In this paper we will examine the underlying fundamentals of different lipidomic experimental approaches including the “shotgun” and “top-down” global approaches, and the more targeted liquid chromatography – or gas chromatography – mass spectrometry approaches. Application of these approaches to the identification of in-born errors of metabolism will be discussed.


Bile Acid Desmosterol Fatty Acid Substituent Exact Mass Measurement Bile Acid Biosynthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by funding from The Royal Society, BBSRC and EPSRC.

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  1. Adachi R, Honma Y, Masuno H, Kawana K, Shimomura I, Yamada S, Makishima M (2005) Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. J Lipid Res 46:46–57PubMedCrossRefGoogle Scholar
  2. Andreyev AY, Fahy E, Guan Z, Kelly S, Li X, McDonald JG, Milne S, Myers D, Park H, Ryan A, Thompson BM, Wang E, Zhao Y, Brown HA, Merrill AH, Raetz CR, Russell DW, Subramaniam S, Dennis EA (2010) Subcellular organelle lipidomics in TLR-4-activated macrophages. J Lipid Res 51:2785–2797PubMedCrossRefGoogle Scholar
  3. Axelson M, Mörk B, Sjövall J (1988) Occurrence of 3 beta-hydroxy-5-cholestenoic acid, 3 beta, 7 alpha-dihydroxy-5-cholestenoic acid, and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid as normal constituents in human blood. J Lipid Res 29:629–641PubMedGoogle Scholar
  4. Axelson M, Sjövall J (1990) Potential bile acid precursors in plasma–possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 36:631–640PubMedCrossRefGoogle Scholar
  5. Bauman DR, Bitmansour AD, McDonald JG, Thompson BM, Liang G, Russell DW (2009) 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proc Natl Acad Sci USA 106:16764–16769PubMedCrossRefGoogle Scholar
  6. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111PubMedCrossRefGoogle Scholar
  7. Beynon JH (1954) Qualitative analysis of organic compounds by mass spectrometry. Nature 174:735CrossRefGoogle Scholar
  8. Björkhem I, Andersson U, Ellis E, Alvelius G, Ellegard L, Diczfalusy U, Sjövall J, Einarsson C (2001) From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24 S-hydroxycholesterol (cerebrosterol) in humans. J Biol Chem 276:37004–37010PubMedCrossRefGoogle Scholar
  9. Bodin K, Andersson U, Rystedt E, Ellis E, Norlin M, Pikuleva I, Eggertsen G, Björkhem I, Diczfalusy U (2002) Metabolism of 4 beta -hydroxycholesterol in humans. J Biol Chem 277:31534–31540PubMedCrossRefGoogle Scholar
  10. Brown M, Dunn WB, Dobson P, Patel Y, Winder CL, Francis-McIntyre S, Begley P, Carroll K, Broadhurst D, Tseng A, Swainston N, Spasic I, Goodacre R, Kell DB (2009) Mass spectrometry tools and metabolite-specific databases for molecular identification in metabolomics. Analyst 134:1322–1332PubMedCrossRefGoogle Scholar
  11. Burkard I, von EA, Rentsch KM (2005) Differentiated quantification of human bile acids in serum by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B 826:147–159PubMedCrossRefGoogle Scholar
  12. Cheng H, Jiang X, Han X (2007) Alterations in lipid homeostasis of mouse dorsal root ganglia induced by apolipoprotein E deficiency: a shotgun lipidomics study. J Neurochem 101:57–76PubMedCrossRefGoogle Scholar
  13. Christie WW, Han X (2010) Lipid extraction, storage and sample handling. In: Lipid Analysis - Isolation, Separation, Identification and Lipidomic Analysis. The Oily Press, Bridgewater, England, pp 55–69Google Scholar
  14. Dennis EA, Brown AH, Deems RA, Glass CK, Merrill AH, Murphy RC, Raetz CR, Subramaniam S, Russell DW, vanNieuwenhze MS, White SH, Witztum JL, Wooley J (2005) The LIPID MAPS approach to lipidomics. In: Feng L, Prestwich G (eds) Functional Lipidomics. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp 1–15CrossRefGoogle Scholar
  15. Dzeletovic S, Breuer O, Lund E, Diczfalusy U (1995) Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem 225:73–80PubMedCrossRefGoogle Scholar
  16. Ejsing CS, Duchoslav E, Sampaio J, Simons K, Bonner R, Thiele C, Ekroos K, Shevchenko A (2006) Automated identification and quantification of glycerophospholipid molecular species by multiple precursor ion scanning. Anal Chem 78:6202–6214PubMedCrossRefGoogle Scholar
  17. Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, Repa JJ (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci USA 100:223–228PubMedCrossRefGoogle Scholar
  18. Graessler J, Schwudke D, Schwarz PE, Herzog R, Shevchenko A, Bornstein SR (2009) Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients. PLoS ONE 4:e6261PubMedCrossRefGoogle Scholar
  19. Griffiths WJ (2003) Tandem mass spectrometry in the study of fatty acids, bile acids, and steroids. Mass Spectrom Rev 22:81–152PubMedCrossRefGoogle Scholar
  20. Griffiths WJ, Hornshaw M, Woffendin G, Baker SF, Lockhart A, Heidelberger S, Gustafsson M, Sjovall J, Wang Y (2008) Discovering oxysterols in plasma: a window on the metabolome. J Proteome Res 7:3602–3612PubMedCrossRefGoogle Scholar
  21. Griffiths WJ, Sjövall J (2010a) Analytical strategies for characterization of bile acid and oxysterol metabolomes. Biochem Biophys Res Commun 396:80–84PubMedCrossRefGoogle Scholar
  22. Griffiths WJ, Sjövall J (2010b) Bile acids: analysis in biological fluids and tissues. J Lipid Res 51:23–41PubMedCrossRefGoogle Scholar
  23. Griffiths WJ, Wang Y (2009) Mass spectrometry: from proteomics to metabolomics and lipidomics. Chem Soc Rev 38:1882–1896PubMedCrossRefGoogle Scholar
  24. Griffiths WJ, Wang Y, Alvelius G, Liu S, Bodin K, Sjövall J (2006) Analysis of oxysterols by electrospray tandem mass spectrometry. J Am Soc Mass Spectrom 17:341–362PubMedCrossRefGoogle Scholar
  25. Gross RW, Han X (2009) Shotgun lipidomics of neutral lipids as an enabling technology for elucidation of lipid-related diseases. Am J Physiol Endocrinol Metab 297:E297–E303PubMedCrossRefGoogle Scholar
  26. Han X, Gross RW (2003) Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: a bridge to lipidomics. J Lipid Res 44:1071–1079PubMedCrossRefGoogle Scholar
  27. Han X, Gross RW (2005) Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. Mass Spectrom Rev 24:367–412PubMedCrossRefGoogle Scholar
  28. Han X, Yang K, Cheng H, Fikes KN, Gross RW (2005) Shotgun lipidomics of phosphoethanolamine-containing lipids in biological samples after one-step in situ derivatization. J Lipid Res 46:1548–1560PubMedCrossRefGoogle Scholar
  29. Han X, Yang K, Gross RW (2008) Microfluidics-based electrospray ionization enhances the intrasource separation of lipid classes and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-throughput platform for shotgun lipidomics. Rapid Commun Mass Spectrom 22:2115–2124PubMedCrossRefGoogle Scholar
  30. Honda A, Yamashita K, Hara T, Ikegami T, Miyazaki T, Shirai M, Xu G, Numazawa M, Matsuzaki Y (2009) Highly sensitive quantification of key regulatory oxysterols in biological samples by LC-ESI-MS/MS. J Lipid Res 50:350–357PubMedCrossRefGoogle Scholar
  31. Hübner G, Crone C, Lindner B (2009) lipID–a software tool for automated assignment of lipids in mass spectra. J Mass Spectrom 44:1676–1683PubMedGoogle Scholar
  32. Hunt AN, Macken M, Koster G, Kohler JA, Postle AD (2008) Diclofenac mediated derangement of neuroblastoma cell lipidomic profiles is accompanied by increased phosphatidylcholine biosynthesis. Adv Enzyme Regul 48:74–87PubMedCrossRefGoogle Scholar
  33. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ (1999) Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci U S A 96:266–271PubMedCrossRefGoogle Scholar
  34. Jiang X, Ory DS, Han X (2007) Characterization of oxysterols by electrospray ionization tandem mass spectrometry after one-step derivatization with dimethylglycine. Rapid Commun Mass Spectrom 21:141–152PubMedCrossRefGoogle Scholar
  35. Karu K, Hornshaw M, Woffendin G, Bodin K, Hamberg M, Alvelius G, Sjövall J, Turton J, Wang Y, Griffiths WJ (2007) Liquid chromatography-mass spectrometry utilizing multi-stage fragmentation for the identification of oxysterols. J Lipid Res 48:976–987PubMedCrossRefGoogle Scholar
  36. Lemonde HA, Custard EJ, Bouquet J, Duran M, Overmars H, Scambler PJ, Clayton PT (2003) Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut 52:1494–1499PubMedCrossRefGoogle Scholar
  37. McDonald JG, Thompson BM, McCrum EC, Russell DW (2007) Extraction and analysis of sterols in biological matrices by high performance liquid chromatography electrospray ionization mass spectrometry. Methods Enzymol 432:145–170PubMedCrossRefGoogle Scholar
  38. Meng LJ, Griffiths WJ, Nazer H, Yang Y, Sjövall J (1997) High levels of (24S)-24-hydroxycholesterol 3-sulfate, 24-glucuronide in the serum and urine of children with severe cholestatic liver disease. J Lipid Res 38:926–934PubMedGoogle Scholar
  39. Nishimaki-Mogami T, Une M, Fujino T, Sato Y, Tamehiro N, Kawahara Y, Shudo K, Inoue K (2004) Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor. J Lipid Res 45:1538–1545PubMedCrossRefGoogle Scholar
  40. Ogundare M, Theofilopoulos S, Lockhart A, Hall LJ, Arenas E, Sjovall J, Brenton AG, Wang Y, Griffiths WJ (2010) Cerebrospinal fluid steroidomics: are bioactive bile acids present in brain? J Biol Chem 285:4666–4679PubMedCrossRefGoogle Scholar
  41. Pulfer M, Murphy RC (2003) Electrospray mass spectrometry of phospholipids. Mass Spectrom Rev 22:332–364PubMedCrossRefGoogle Scholar
  42. Quehenberger O, Armando AM, Brown AH, Milne SB, Myers DS, Merrill AH, Bandyopadhyay S, Jones KN, Kelly S, Shaner RL, Sullards CM, Wang E, Murphy RC, Barkley RM, Leiker TJ, Raetz CR, Guan Z, Laird GM, Six DA, Russell DW, McDonald JG, Subramaniam S, Fahy E and Dennis EA (2010) Lipidomics reveals a remarkable diversity of lipids in human plasma. J. Lipid Res 51:3299–3305PubMedCrossRefGoogle Scholar
  43. Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL (2007) Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. Proc Natl Acad Sci USA 104:6511–6518PubMedCrossRefGoogle Scholar
  44. Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72:137–174PubMedCrossRefGoogle Scholar
  45. Ryhage R, Stenhagan E (1960) Mass spectrometry in lipid research. J Lipid Res 1:361–390PubMedGoogle Scholar
  46. Sandra K, Pereira AS, Vanhoenacker G, David F, Sandra P (2010) Comprehensive blood plasma lipidomics by liquid chromatography/quadrupole time-of-flight mass spectrometry. J Chromatogr A 1217:4087–4099PubMedCrossRefGoogle Scholar
  47. Schiller J, Suss R, Fuchs B, Muller M, Zschornig O, Arnold K (2007) MALDI-TOF MS in lipidomics. Front Biosci 12:2568–2579PubMedCrossRefGoogle Scholar
  48. Schroepfer GJ (2000) Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 80:361–554PubMedGoogle Scholar
  49. Schwudke D, Hannich JT, Surendranath V, Grimard V, Moehring T, Burton L, Kurzchalia T, Shevchenko A (2007) Top-down lipidomic screens by multivariate analysis of high-resolution survey mass spectra. Anal Chem 79:4083–4093PubMedCrossRefGoogle Scholar
  50. Setchell KD, Heubi JE (2006) Defects in bile acid biosynthesis–diagnosis and treatment. J Pediatr Gastroenterol Nutr 43(Suppl 1):S17–S22PubMedGoogle Scholar
  51. Shefer S, Cheng FW, Dayal B, Hauser S, Tint GS, Salen G, Mosbach EH (1976) A 25-hydroxylation pathway of cholic acid biosynthesis in man and rat. J Clin Invest 57:897–903PubMedCrossRefGoogle Scholar
  52. Sjövall J (2004) Fifty years with bile acids and steroids in health and disease. Lipids 39:703–722PubMedGoogle Scholar
  53. Sjövall J, Griffiths WJ, Setchell KD, Mano N, Goto J (2010) Analysis of bile acids. In: Makin HJ, Gower DB (eds) Steroid Analysis. Springer, Heidelberg, pp 837–966CrossRefGoogle Scholar
  54. Subramaniam P, Clayton PT, Portmann BC, Mieli-Vergani G, Hadzic N (2010) Variable clinical spectrum of the most common inborn error of bile acid metabolism–3beta-hydroxy-Delta 5–C27-steroid dehydrogenase deficiency. J Pediatr Gastroenterol Nutr 50:61–66PubMedCrossRefGoogle Scholar
  55. Wang Y, Sousa KM, Bodin K, Theofilopoulos S, Sacchetti P, Hornshaw M, Woffendin G, Karu K, Sjovall J, Arenas E, Griffiths WJ (2009) Targeted lipidomic analysis of oxysterols in the embryonic central nervous system. Mol Biosyst 5:529–541PubMedCrossRefGoogle Scholar
  56. Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B, Hau DD, Psychogios N, Dong E, Bouatra S, Mandal R, Sinelnikov I, Xia J, Jia L, Cruz JA, Lim E, Sobsey CA, Shrivastava S, Huang P, Liu P, Fang L, Peng J, Fradette R, Cheng D, Tzur D, Clements M, Lewis A, De SA, Zuniga A, Dawe M, Xiong Y, Clive D, Greiner R, Nazyrova A, Shaykhutdinov R, Li L, Vogel HJ, Forsythe I (2009) HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res 37:D603–D610PubMedCrossRefGoogle Scholar
  57. Yang K, Cheng H, Gross RW, Han X (2009) Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem 81:4356–4368PubMedCrossRefGoogle Scholar
  58. Zelena E, Dunn WB, Broadhurst D, Francis-McIntyre S, Carroll KM, Begley P, O'Hagan S, Knowles JD, Halsall A, Wilson ID, Kell DB (2009) Development of a robust and repeatable UPLC-MS method for the long-term metabolomic study of human serum. Anal Chem 81:1357–1364PubMedCrossRefGoogle Scholar
  59. Zhang J, Xue Y, Jondal M, Sjovall J (1997) 7alpha-Hydroxylation and 3-dehydrogenation abolish the ability of 25-hydroxycholesterol and 27-hydroxycholesterol to induce apoptosis in thymocytes. Eur J Biochem 247:129–135PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • William J. Griffiths
    • 1
  • Michael Ogundare
    • 1
  • Christopher M. Williams
    • 2
  • Yuqin Wang
    • 1
  1. 1.Institute of Mass SpectrometrySchool of Medicine, Grove Building, Swansea UniversitySwanseaUK
  2. 2.EPSRC National Mass Spectrometry Service CentreSchool of Medicine, Grove Building, Swansea UniversitySwanseaUK

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