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Mass Spectrometry Imaging of Cholesterol and Oxysterols

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Implication of Oxysterols and Phytosterols in Aging and Human Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1440))

Abstract

Mass spectrometry imaging (MSI) is a new technique in the toolbox of the analytical biochemist. It allows the generation of a compound-specific image from a tissue slice where a measure of compound abundance is given pixel by pixel, usually displayed on a color scale. As mass spectra are recorded at each pixel, the data can be interrogated to generate images of multiple different compounds all in the same experiment. Mass spectrometry (MS) requires the ionization of analytes, but cholesterol and other neutral sterols tend to be poorly ionized by the techniques employed in most MSI experiments, so despite their high abundance in mammalian tissues, cholesterol is poorly represented in the MSI literature. In this chapter, we discuss some of the MSI studies where cholesterol has been imaged and introduce newer methods for its analysis by MSI. Disturbed cholesterol metabolism is linked to many disorders, and the potential of MSI to study cholesterol, its precursors, and its metabolites in animal models and from human biopsies will be discussed.

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References

  • Abdel-Khalik J, Yutuc E, Crick PJ, Gustafsson JA, Warner M, Roman G, Talbot K, Gray E, Griffiths WJ, Turner MR, Wang Y (2017) Defective cholesterol metabolism in amyotrophic lateral sclerosis. J Lipid Res 58:267–278

    Article  CAS  PubMed  Google Scholar 

  • Almeida R, Berzina Z, Arnspang EC, Baumgart J, Vogt J, Nitsch R, Ejsing CS (2015) Quantitative spatial analysis of the mouse brain lipidome by pressurized liquid extraction surface analysis. Anal Chem 87:1749–1756

    Article  CAS  PubMed  Google Scholar 

  • Angelini R, Yutuc E, Wyatt MF, Newton J, Yusuf FA, Griffiths L, Cooze BJ, El Assad D, Frache G, Rao W, Allen LB, Korade Z, Nguyen TTA, Rathnayake RAC, Cologna SM, Howell OW, Clench MR, Wang Y, Griffiths WJ (2021) Visualizing cholesterol in the brain by on-tissue derivatization and quantitative mass spectrometry imaging. Anal Chem 93:4932–4943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bai H, Linder KE, Muddiman DC (2021) Three-dimensional (3D) imaging of lipids in skin tissues with infrared matrix-assisted laser desorption electrospray ionization (MALDESI) mass spectrometry. Anal Bioanal Chem 413:2793–2801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barre FP, Flinders B, Garcia JP, Jansen I, Huizing LR, Porta T, Creemers LB, Heeren RM, Cillero-Pastor B (2016) Derivatization strategies for the detection of triamcinolone acetonide in cartilage by using matrix-assisted laser desorption/ionization mass spectrometry imaging. Anal Chem 88:12051–12059

    Article  CAS  PubMed  Google Scholar 

  • Berry KA, Hankin JA, Barkley RM, Spraggins JM, Caprioli RM, Murphy RC (2011) MALDI imaging of lipid biochemistry in tissues by mass spectrometry. Chem Rev 111:6491–6512

    Article  PubMed  PubMed Central  Google Scholar 

  • Brunet MA, Kraft ML (2023) Toward understanding the subcellular distributions of cholesterol and sphingolipids using high-resolution NanoSIMS imaging. Acc Chem Res 56:752–762

    Article  CAS  PubMed  Google Scholar 

  • Cobice DF, Mackay CL, Goodwin RJ, McBride A, Langridge-Smith PR, Webster SP, Walker BR, Andrew R (2013) Mass spectrometry imaging for dissecting steroid intracrinology within target tissues. Anal Chem 85:11576–11584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cobice DF, Livingstone DE, Mackay CL, Goodwin RJ, Smith LB, Walker BR, Andrew R (2016) Spatial localization and quantitation of androgens in mouse testis by mass spectrometry imaging. Anal Chem 88:10362–10367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cobice DF, Livingstone DEW, McBride A, MacKay CL, Walker BR, Webster SP, Andrew R (2018) Quantification of 11beta-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice. Biochem Pharmacol 148:88–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cologna SM (2019) Mass spectrometry imaging of cholesterol. Adv Exp Med Biol 1115:155–166

    Article  CAS  PubMed  Google Scholar 

  • Cooks RG, Ouyang Z, Takats Z, Wiseman JM (2006) Detection technologies. Ambient mass spectrometry. Science 311:1566–1570

    Article  CAS  PubMed  Google Scholar 

  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  CAS  PubMed  Google Scholar 

  • Crick PJ, Griffiths WJ, Zhang J, Beibel M, Abdel-Khalik J, Kuhle J, Sailer AW, Wang Y (2017) Reduced plasma levels of 25-hydroxycholesterol and increased cerebrospinal fluid levels of bile acid precursors in multiple sclerosis patients. Mol Neurobiol 54:8009–8020

    Article  CAS  PubMed  Google Scholar 

  • Dietschy JM, Turley SD (2004) Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45:1375–1397

    Article  CAS  PubMed  Google Scholar 

  • Ellis SR, Soltwisch J (2023) Mass spectrometry imaging of lipids. In: Mass spectrometry for lipidomics, pp 117–150

    Chapter  Google Scholar 

  • Ellis SR, Soltwisch J, Paine MRL, Dreisewerd K, Heeren RMA (2017) Laser post-ionisation combined with a high resolving power orbitrap mass spectrometer for enhanced MALDI-MS imaging of lipids. Chem Commun 53:7246–7249

    Article  CAS  Google Scholar 

  • Frisz JF, Klitzing HA, Lou K, Hutcheon ID, Weber PK, Zimmerberg J, Kraft ML (2013) Sphingolipid domains in the plasma membranes of fibroblasts are not enriched with cholesterol. J Biol Chem 288:16855–16861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Girard A, Sandulesco G (1936) Sur une nouvelle série de réactifs du groupe carbonyle, leur utilisation à l'extraction des substances cétoniques et à la caractérisation microchimique des aldéhydes et cétones. Helv Chim Acta 19:1095–1107

    Article  CAS  Google Scholar 

  • Griffiths WJ, Wang Y, Alvelius G, Liu S, Bodin K, Sjovall J (2006) Analysis of oxysterols by electrospray tandem mass spectrometry. J Am Soc Mass Spectrom 17:341–362

    Article  CAS  PubMed  Google Scholar 

  • Griffiths WJ, Yutuc E, Davies D, Dickson A, Angelini R, El Assad D, Frache G, Wang Y (2020) Lipidomics basics. In: Griffiths WJ, Wang Y (eds) Lipidomics: current and emerging techniques. Royal Society of Chemistry, Cambridge, pp 1–24

    Chapter  Google Scholar 

  • Haider A, Zhao C, Wang L, Xiao Z, Rong J, Xia X, Chen Z, Pfister SK, Mast N, Yutuc E, Chen J, Li Y, Shao T, Warnock GI, Dawoud A, Connors TR, Oakley DH, Wei H, Wang J, Zheng Z, Xu H, Davenport AT, Daunais JB, Van RS, Shao Y, Wang Y, Zhang MR, Gebhard C, Pikuleva I, Levey AI, Griffiths WJ, Liang SH (2022) Assessment of cholesterol homeostasis in the living human brain. Sci Transl Med 14:eadc9967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hall Z, Chu Y, Griffin JL (2017) Liquid extraction surface analysis mass spectrometry method for identifying the presence and severity of nonalcoholic fatty liver disease. Anal Chem 89:5161–5170

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Liu X, Liu D, Zhang X, Zhang L, Le W, Zhang Y (2022) Pyrylium-based derivatization for rapid labeling and enhanced detection of cholesterol in mass spectrometry imaging. J Am Soc Mass Spectrom 33:2310–2318

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood KI, Odenkirk MT, Baker ES (2023) Ion mobility spectrometry. In: Mass spectrometry for lipidomics, pp 151–182

    Chapter  Google Scholar 

  • Lazar AN, Bich C, Panchal M, Desbenoit N, Petit VW, Touboul D, Dauphinot L, Marquer C, Laprévote O, Brunelle A, Duyckaerts C (2013) Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients. Acta Neuropathol 125:133–144

    Article  CAS  PubMed  Google Scholar 

  • Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176

    Article  CAS  PubMed  Google Scholar 

  • Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327:46–50

    Article  CAS  PubMed  Google Scholar 

  • Lütjohann D, Stroick M, Bertsch T, Kühl S, Lindenthal B, Thelen K, Andersson U, Björkhem I, Bergmann KV, Fassbender K (2004) High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in Guinea pigs. Steroids 69:431–438

    Article  PubMed  Google Scholar 

  • Mackay CLL, Soltwisch J, Heijs B, Smith KW, Cruickshank FL, Nyhuis A, Dreisewerd K, Cobice D (2021) Spatial distribution of isobaric androgens in target tissues using chemical derivatization and MALDI-2 on a trapped ion mobility quadrupole time-of-flight instrument. RSC Adv 11:33916–33925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacLachlan J, Wotherspoon AT, Ansell RO, Brooks CJ (2000) Cholesterol oxidase: sources, physical properties and analytical applications. J Steroid Biochem Mol Biol 72:169–195

    Article  CAS  PubMed  Google Scholar 

  • Nezhad ZS, Salazar JP, Pryce RS, Munter LM, Chaurand P (2022) Absolute quantification of cholesterol from thin tissue sections by silver-assisted laser desorption ionization mass spectrometry imaging. Anal Bioanal Chem 414:6947–6954

    Article  CAS  PubMed  Google Scholar 

  • Nikolova-Damyanova B (2009) Retention of lipids in silver ion high-performance liquid chromatography: facts and assumptions. J Chromatogr A 1216:1815–1824

    Article  CAS  PubMed  Google Scholar 

  • Patti GJ, Shriver LP, Wassif CA, Woo HK, Uritboonthai W, Apon J, Manchester M, Porter FD, Siuzdak G (2010) Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome. Neuroscience 170:858–864

    Article  CAS  PubMed  Google Scholar 

  • Roberg-Larsen H, Strand MF, Grimsmo A, Olsen PA, Dembinski JL, Rise F, Lundanes E, Greibrokk T, Krauss S, Wilson SR (2012) High sensitivity measurements of active oxysterols with automated filtration/filter backflush-solid phase extraction-liquid chromatography-mass spectrometry. J Chromatogr A 1255:291–297

    Article  CAS  PubMed  Google Scholar 

  • Schroepfer GJ Jr (2000) Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 80:361–554

    Article  CAS  PubMed  Google Scholar 

  • Shimma S, Kumada HO, Taniguchi H, Konno A, Yao I, Furuta K, Matsuda T, Ito S (2016) Microscopic visualization of testosterone in mouse testis by use of imaging mass spectrometry. Anal Bioanal Chem 408:7607–7615

    Article  CAS  PubMed  Google Scholar 

  • Sjovall J (2004) Fifty years with bile acids and steroids in health and disease. Lipids 39:703–722

    Article  PubMed  Google Scholar 

  • Soltwisch J, Kettling H, Vens-Cappell S, Wiegelmann M, Muthing J, Dreisewerd K (2015) Mass spectrometry imaging with laser-induced postionization. Science 348:211–215

    Article  CAS  PubMed  Google Scholar 

  • Spengler B (2015) Mass spectrometry imaging of biomolecular information. Anal Chem 87:64–82

    Article  CAS  PubMed  Google Scholar 

  • Stoeckli M, Chaurand P, Hallahan DE, Caprioli RM (2001) Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues. Nat Med 7:493–496

    Article  CAS  PubMed  Google Scholar 

  • Takeo E, Sugiura Y, Uemura T, Nishimoto K, Yasuda M, Sugiyama E, Ohtsuki S, Higashi T, Nishikawa T, Suematsu M, Fukusaki E, Shimma S (2019) Tandem mass spectrometry imaging reveals distinct accumulation patterns of steroid structural isomers in human adrenal glands. Anal Chem 91:8918–8925

    Article  CAS  PubMed  Google Scholar 

  • Tobias F, Olson MT, Cologna SM (2018) Mass spectrometry imaging of lipids: untargeted consensus spectra reveal spatial distributions in Niemann-Pick disease type C1. J Lipid Res 59:2446–2455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trim PJ, Atkinson SJ, Princivalle AP, Marshall PS, West A, Clench MR (2008) Matrix-assisted laser desorption/ionisation mass spectrometry imaging of lipids in rat brain tissue with integrated unsupervised and supervised multivariant statistical analysis. Rapid Commun Mass Spectrom 22:1503–1509

    Article  CAS  PubMed  Google Scholar 

  • Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M, Mariotti C, Di Donato S, Corsini A, Bates G, Pruss R, Olson JM, Sipione S, Tartari M, Cattaneo E (2005) Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease. J Neurosci 25:9932–9939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Griffiths WJ (2020) Chapter 6 derivatisation for direct infusion– and liquid chromatography–mass spectrometry. In: Lipidomics: current and emerging techniques. The Royal Society of Chemistry, pp 122–147

    Chapter  Google Scholar 

  • Wang X, Hou Y, Hou Z, Xiong W, Huang G (2019) Mass spectrometry imaging of brain cholesterol and metabolites with Trifluoroacetic acid-enhanced desorption electrospray ionization. Anal Chem 91:2719–2726

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Luo Z, Li C, Huang X, Shiroma EJ, Simonsick EM, Chen H (2021a) Blood cholesterol decreases as Parkinson's disease develops and progresses. J Parkinsons Dis 11:1177–1186

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Yutuc E, Griffiths WJ (2021b) Neuro-oxysterols and neuro-sterols as ligands to nuclear receptors, GPCRs, ligand-gated ion channels and other protein receptors. Br J Pharmacol 178:3176–3193

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Zang Q, Zhu Y, Liu J, Li X, Tu X, Li X, Abliz Z, Zhang R (2023) On-tissue chemical oxidation followed by derivatization for mass spectrometry imaging enables visualization of primary and secondary hydroxyl-containing metabolites in biological tissues. Anal Chem 95:1975–1984

    Article  CAS  Google Scholar 

  • Wheeler OH (1968) The Girard reagents. J Chem Educ 45

    Google Scholar 

  • Wu C, Ifa DR, Manicke NE, Cooks RG (2009) Rapid, direct analysis of cholesterol by charge labeling in reactive desorption electrospray ionization. Anal Chem 81:7618–7624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L, Kliman M, Forsythe JG, Korade Z, Hmelo AB, Porter NA, McLean JA (2015) Profiling and imaging ion mobility-mass spectrometry analysis of cholesterol and 7-dehydrocholesterol in cells via sputtered silver MALDI. J Am Soc Mass Spectrom 26:924–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang E, Fournelle F, Chaurand P (2020) Silver spray deposition for AgLDI imaging MS of cholesterol and other olefins on thin tissue sections. J Mass Spectrom 55:e4428

    Article  CAS  PubMed  Google Scholar 

  • Yutuc E, Angelini R, Baumert M, Mast N, Pikuleva I, Newton J, Clench MR, Skibinski DOF, Howell OW, Wang Y, Griffiths WJ (2020) Localization of sterols and oxysterols in mouse brain reveals distinct spatial cholesterol metabolism. Proc Natl Acad Sci U S A 117:5749–5760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yutuc E, Dickson AL, Pacciarini M, Griffiths L, Baker PRS, Connell L, Öhman A, Forsgren L, Trupp M, Vilarinho S, Khalil Y, Clayton PT, Sari S, Dalgic B, Höflinger P, Schöls L, Griffiths WJ, Wang Y (2021) Deep mining of oxysterols and cholestenoic acids in human plasma and cerebrospinal fluid: quantification using isotope dilution mass spectrometry. Anal Chim Acta 1154:338259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zecchi R, Franceschi P, Tigli L, Amidani D, Catozzi C, Ricci F, Salomone F, Pieraccini G, Pioselli B, Mileo V (2021) Sample preparation strategy for the detection of steroid-like compounds using MALDI mass spectrometry imaging: pulmonary distribution of budesonide as a case study. Anal Bioanal Chem 413:4363–4371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Guo S, Zhang M, Liu Y, Chen T, Li Z (2017) Mass spectrometry imaging of small molecules in biological tissues using graphene oxide as a matrix. Anal Chim Acta 962:52–59

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Swansea University Medical School, Swansea, Wales, UK

    William J. Griffiths, Eylan Yutuc & Yuqin Wang

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  1. William J. Griffiths
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  2. Eylan Yutuc
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  3. Yuqin Wang
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Correspondence to William J. Griffiths .

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Editors and Affiliations

  1. Department of Biochemistry (Biochemstry of the peroxisome, inflammation and lipid metabolism), University of Bourgogne & Inserm, Dijon, France

    Gérard Lizard

Ethics declarations

We are indebted to Drs Joyce Yau, Shazia Khan, and Ruth Andrew from the University of Edinburgh for providing mouse brain tissue. We thank Drs Lauren Griffiths and Roberto Angelini for their work on MALDI-MSI in Swansea and Dr. Malcolm Clench, Sheffield Hallam University, for inspiring us to join the MSI field. This work was supported by the BBSRC, part of UKRI. Members of the European Network for Oxysterol Research (ENOR, https://www.oxysterols.net/) are thanked for informative discussions.

Declaration of Competing Interests

The authors declare the following financial interests, which may be considered potential competing interests: WJG and YW are listed as inventors on the patent “Kit and method for quantitative detection of steroids” US9851368B2. WJG, EY, and YW are shareholders in CholesteniX Ltd.

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Griffiths, W.J., Yutuc, E., Wang, Y. (2024). Mass Spectrometry Imaging of Cholesterol and Oxysterols. In: Lizard, G. (eds) Implication of Oxysterols and Phytosterols in Aging and Human Diseases. Advances in Experimental Medicine and Biology, vol 1440. Springer, Cham. https://doi.org/10.1007/978-3-031-43883-7_5

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