Lipidomics of Peroxisomal Disorders

  • Kotaro HamaEmail author
  • Yuko Fujiwara
  • Kazuaki Yokoyama


Peroxisomes are cytoplasmic organelles that play a key role in metabolic and synthetic processes of various lipids. Peroxisomal disorders are caused by defects in peroxisome biogenesis or a peroxisomal single enzyme, and lead to multiple pathological features such as enlarged ventricles, demyelination, hearing loss and psychomotor retardation. Specific lipid profiles are observed for each peroxisomal disorder, which reflects the abnormal process in metabolism or synthesis of lipids. Therefore, lipid analysis of biological samples (e.g. blood plasma and fibroblasts) from patients is essential for the precise diagnosis and identification of responsible genes of peroxisomal disorders. Recent advances in mass spectrometry have enabled both identification and simultaneous quantification of a large number of lipid species. In this review, we introduce the principles of ‘lipidomics’ and the latest research using the lipidomic approach to study peroxisomal disorders.


Lipidomics LC-ESI-MS PBD X-ALD 



ATP-binding cassette sub-family D1


A-methylacyl-CoA racemase


Acyl-CoA oxidase


D-bifunctional protein


Dihydroxycholestanoic acid


Electrospray ionization


Gas chromatography–mass spectrometry


Imaging mass spectrometry


Infantile Refsum’s disease


Liquid chromatography


Multiple reaction monitoring


Mass spectrometry


Tandem mass


Neonatal adrenoleukodystrophy


Peroxisome biogenesis disorders








Rhizomelic chondrodysplasia punctata


Sterol carrier protein X


Trihydroxycholestanoic acid




Very long chain fatty acids


X-linked adrenoleukodystrophy


Zellweger syndrome


Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Abe Y, Honsho M, Nakanishi H, Taguchi R, Fujiki Y (2014) Very-long-chain polyunsaturated fatty acids accumulate in phosphatidylcholine of fibroblasts from patients with Zellweger syndrome and acyl-CoA oxidase1 deficiency. Biochim Biophys Acta 1841:610–619CrossRefGoogle Scholar
  2. Armangue T, Orsini JJ, Takanohashi A, Gavazzi F, Conant A, Ulrick N, Morrissey MA, Nahhas N, Helman G, Gordish-Dressman H, Orcesi S, Tonduti D, Stutterd C, van Haren K, Toro C, Iglesias AD, van der Knaap MS, Goldbach Mansky R, Moser AB, Jones RO, Vanderver A (2017) Neonatal detection of Aicardi Goutieres syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots. Mol Genet Metab 122(3):134–139CrossRefGoogle Scholar
  3. Braverman N, Steel G, Obie C, Moser A, Moser H, Gould SJ, Valle D (1997) Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet 15:369–376CrossRefGoogle Scholar
  4. Cajka T, Fiehn O (2016) Toward merging untargeted and targeted methods in mass spectrometry-based metabolomics and lipidomics. Anal Chem 88:524–545CrossRefGoogle Scholar
  5. de Vet EC, Ijlst L, Oostheim W, Wanders RJ, van den Bosch H (1998) Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency. J Biol Chem 273:10296–10301CrossRefGoogle Scholar
  6. Ferdinandusse S, Overmars H, Denis S, Waterham HR, Wanders RJ, Vreken P (2001) Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal alpha-methylacyl-CoA racemase deficiency. J Lipid Res 42:137–141PubMedGoogle Scholar
  7. Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, Reith W, Haas D, Wanders RJ, Duran M, Marziniak M (2006) Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet 78:1046–1052CrossRefGoogle Scholar
  8. Ferdinandusse S, Falkenberg KD, Koster J, Mooyer PA, Jones R, van Roermund CWT, Pizzino A, Schrader M, Wanders RJA, Vanderver A, Waterham HR (2017) ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J Med Genet 54:330–337CrossRefGoogle Scholar
  9. Goto-Inoue N, Hayasaka T, Zaima N, Setou M (2011) Imaging mass spectrometry for lipidomics. Biochim Biophys Acta 1811:961–969CrossRefGoogle Scholar
  10. Hama K, Nagai T, Nishizawa C, Ikeda K, Morita M, Satoh N, Nakanishi H, Imanaka T, Shimozawa N, Taguchi R, Inoue K, Yokoyama K (2013) Molecular species of phospholipids with very long chain fatty acids in skin fibroblasts of Zellweger syndrome. Lipids 48:1253–1267CrossRefGoogle Scholar
  11. Hama K, Fujiwara Y, Morita M, Yamazaki F, Nakashima Y, Takei S, Takashima S, Setou M, Shimozawa N, Imanaka T, Yokoyama K (2018) Profiling and imaging of phospholipids in brains of Abcd1-deficient mice. Lipids 53:85–102CrossRefGoogle Scholar
  12. Hanson RF, Szczepanik-VanLeeuwen P, Williams GC, Grabowski G, Sharp HL (1979) Defects of bile acid synthesis in Zellweger’s syndrome. Science 203:1107–1108CrossRefGoogle Scholar
  13. Herzog K, Pras-Raves ML, Vervaart MA, Luyf AC, van Kampen AH, Wanders RJ, Waterham HR, Vaz FM (2016) Lipidomic analysis of fibroblasts from Zellweger spectrum disorder patients identifies disease-specific phospholipid ratios. J Lipid Res 57:1447–1454CrossRefGoogle Scholar
  14. Herzog K, Pras-Raves ML, Ferdinandusse S, Vervaart MAT, Luyf ACM, van Kampen AHC, Wanders RJA, Waterham HR, Vaz FM (2018) Plasma lipidomics as a diagnostic tool for peroxisomal disorders. J Inherit Metab Dis 41(3):489–498CrossRefGoogle Scholar
  15. Hubbard WC, Moser AB, Tortorelli S, Liu A, Jones D, Moser H (2006) Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings. Mol Genet Metab 89:185–187CrossRefGoogle Scholar
  16. Hubbard WC, Moser AB, Liu AC, Jones RO, Steinberg SJ, Lorey F, Panny SR, Vogt RF Jr, Macaya D, Turgeon CT, Tortorelli S, Raymond GV (2009) Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab 97:212–220CrossRefGoogle Scholar
  17. Jang J, Park S, Jin Hur H, Cho HJ, Hwang I, Pyo Kang Y, Im I, Lee H, Lee E, Yang W, Kang HC, Won Kwon S, Yu JW, Kim DW (2016) 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat Commun 7:13129CrossRefGoogle Scholar
  18. Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M (2016) Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol 12:606–615CrossRefGoogle Scholar
  19. Lee DK, Long NP, Jung J, Kim TJ, Na E, Kang YP, Kwon SW, Jang J (2019) Integrative lipidomic and transcriptomic analysis of X-linked adrenoleukodystrophy reveals distinct lipidome signatures between adrenomyeloneuropathy and childhood cerebral adrenoleukodystrophy. Biochem Biophys Res Commun 508(2):563–569CrossRefGoogle Scholar
  20. Moser AB, Jones DS, Raymond GV, Moser HW (1999) Plasma and red blood cell fatty acids in peroxisomal disorders. Neurochem Res 24:187–197CrossRefGoogle Scholar
  21. Moser H, Smith KD, Watkins PA, Powers J, Moser AB (2001) X-linked adrenoleukodystrophy, the metabolic and molecular bases of inherited disease, vol II, 8th edn. McGraw-Hill, New York, pp 3257–3301Google Scholar
  22. Mosser J, Douar AM, Sarde CO, Kioschis P, Feil R, Moser H, Poustka AM, Mandel JL, Aubourg P (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361:726–730CrossRefGoogle Scholar
  23. Nury T, Zarrouk A, Ragot K, Debbabi M, Riedinger JM, Vejux A, Aubourg P, Lizard G (2017) 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: potential roles of 7-ketocholesterol in the pathophysiology of X-ALD. J Steroid Biochem Mol Biol 169:123–136CrossRefGoogle Scholar
  24. Ofman R, Hettema EH, Hogenhout EM, Caruso U, Muijsers AO, Wanders RJ (1998) Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. Hum Mol Genet 7:847–853CrossRefGoogle Scholar
  25. Parmentier GG, Janssen GA, Eggermont EA, Eyssen HJ (1979) C27 bile acids in infants with coprostanic acidemia and occurrence of a 3 alpha,7 alpha,12 alpha-tridhydroxy-5 beta-C29 dicarboxylic bile acid as a major component in their serum. Eur J Biochem 102:173–183CrossRefGoogle Scholar
  26. Schutgens RB, Wanders RJ, Heymans HS, Schram AW, Tager JM, Schrakamp G, van den Bosch H (1987) Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment. J Inherit Metab Dis 10(Suppl 1):33–45CrossRefGoogle Scholar
  27. Shimozawa N (2007) Molecular and clinical aspects of peroxisomal diseases. J Inherit Metab Dis 30:193–197CrossRefGoogle Scholar
  28. Sugiura Y, Konishi Y, Zaima N, Kajihara S, Nakanishi H, Taguchi R, Setou M (2009) Visualization of the cell-selective distribution of PUFA-containing phosphatidylcholines in mouse brain by imaging mass spectrometry. J Lipid Res 50:1776–1788CrossRefGoogle Scholar
  29. Sun N, Wu Y, Nanba K, Sbiera S, Kircher S, Kunzke T, Aichler M, Berezowska S, Reibetanz J, Rainey WE, Fassnacht M, Walch A, Kroiss M (2018) High resolution tissue mass spectrometry imaging reveals a refined functional anatomy of the human adult adrenal gland. Endocrinology 159(3):1511–1524CrossRefGoogle Scholar
  30. Suzuki Y, Shimozawa N, Imamura A, Fukuda S, Zhang Z, Orii T, Kondo N (2001) Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. J Inherit Metab Dis 24:151–165CrossRefGoogle Scholar
  31. Taguchi R, Houjou T, Nakanishi H, Yamazaki T, Ishida M, Imagawa M, Shimizu T (2005) Focused lipidomics by tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 823:26–36CrossRefGoogle Scholar
  32. Takashima S, Toyoshi K, Itoh T, Kajiwara N, Honda A, Ohba A, Takemoto S, Yoshida S, Shimozawa N (2017) Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. Mol Genet Metab 120(3):255–268CrossRefGoogle Scholar
  33. Takemoto Y, Suzuki Y, Horibe R, Shimozawa N, Wanders RJ, Kondo N (2003) Gas chromatography/mass spectrometry analysis of very long chain fatty acids, docosahexaenoic acid, phytanic acid and plasmalogen for the screening of peroxisomal disorders. Brain and Development 25:481–487CrossRefGoogle Scholar
  34. Theda C, Gibbons K, Defor TE, Donohue PK, Golden WC, Kline AD, Gulamali-Majid F, Panny SR, Hubbard WC, Jones RO, Liu AK, Moser AB, Raymond GV (2014) Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible. Mol Genet Metab 111:55–57CrossRefGoogle Scholar
  35. Vogel BH, Bradley SE, Adams DJ, D’Aco K, Erbe RW, Fong C, Iglesias A, Kronn D, Levy P, Morrissey M, Orsini J, Parton P, Pellegrino J, Saavedra-Matiz CA, Shur N, Wasserstein M, Raymond GV, Caggana M (2015) Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab 114:599–603CrossRefGoogle Scholar
  36. Wood PL, Khan MA, Smith T, Ehrmantraut G, Jin W, Cui W, Braverman NE, Goodenowe DB (2011) In vitro and in vivo plasmalogen replacement evaluations in rhizomelic chrondrodysplasia punctata and Pelizaeus-Merzbacher disease using PPI-1011, an ether lipid plasmalogen precursor. Lipids Health Dis 10:182CrossRefGoogle Scholar
  37. Yagita Y, Shinohara K, Abe Y, Nakagawa K, Al-Owain M, Alkuraya FS, Fujiki Y (2017) Deficiency of a retinal dystrophy protein, acyl-CoA binding domain-containing 5 (ACBD5), impairs peroxisomal beta-oxidation of very-long-chain fatty acids. J Biol Chem 292:691–705CrossRefGoogle Scholar
  38. Yore MM, Syed I, Moraes-Vieira PM, Zhang T, Herman MA, Homan EA, Patel RT, Lee J, Chen S, Peroni OD, Dhaneshwar AS, Hammarstedt A, Smith U, McGraw TE, Saghatelian A, Kahn BB (2014) Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159:318–332CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Faculty of Pharma-SciencesTeikyo UniversityTokyoJapan

Personalised recommendations