Lipidomics

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Examples of various lipid species. Lipid examples.png
Examples of various lipid species.

Lipidomics is the large-scale study of pathways and networks of cellular lipids in biological systems [1] [2] [3] The word "lipidome" is used to describe the complete lipid profile within a cell, tissue, organism, or ecosystem and is a subset of the "metabolome" which also includes other major classes of biological molecules (such as amino acids, sugars, glycolysis & TCA intermediates, and nucleic acids). Lipidomics is a relatively recent research field that has been driven by rapid advances in technologies such as mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, fluorescence spectroscopy, dual polarisation interferometry and computational methods, coupled with the recognition of the role of lipids in many metabolic diseases such as obesity, atherosclerosis, stroke, hypertension and diabetes. This rapidly expanding field [4] complements the huge progress made in genomics and proteomics, all of which constitute the family of systems biology.

Contents

Lipidomics research involves the identification and quantification of the thousands of cellular lipid molecular species and their interactions with other lipids, proteins, and other metabolites. Investigators in lipidomics examine the structures, functions, interactions, and dynamics of cellular lipids and the changes that occur during perturbation of the system.

Han and Gross [5] first defined the field of lipidomics through integrating the specific chemical properties inherent in lipid molecular species with a comprehensive mass spectrometric approach. Although lipidomics is under the umbrella of the more general field of "metabolomics", lipidomics is itself a distinct discipline due to the uniqueness and functional specificity of lipids relative to other metabolites.

In lipidomic research, a vast amount of information quantitatively describing the spatial and temporal alterations in the content and composition of different lipid molecular species is accrued after perturbation of a cell through changes in its physiological or pathological state. Information obtained from these studies facilitates mechanistic insights into changes in cellular function. Therefore, lipidomic studies play an essential role in defining the biochemical mechanisms of lipid-related disease processes through identifying alterations in cellular lipid metabolism, trafficking and homeostasis. The growing attention on lipid research is also seen from the initiatives underway of the LIPID Metabolites And Pathways Strategy (LIPID MAPS Consortium). [6] and The European Lipidomics Initiative (ELIfe). [7]

Structural diversity of lipids

Lipids are a diverse and ubiquitous group of compounds which have many key biological functions, such as acting as structural components of cell membranes, serving as energy storage sources and participating in signaling pathways. Lipids may be broadly defined as hydrophobic or amphipathic small molecules that originate entirely or in part from two distinct types of biochemical subunits or "building blocks": ketoacyl and isoprene groups. [8] The huge structural diversity found in lipids arises from the biosynthesis of various combinations of these building blocks. For example, glycerophospholipids are composed of a glycerol backbone linked to one of approximately 10 possible headgroups and also to 2 fatty acyl/alkyl chains, which in turn may have 30 or more different molecular structures. In practice, not all possible permutations are detected experimentally, due to chain preferences depending on the cell type and also to detection limits - nevertheless several hundred distinct glycerophospholipid molecular species have been detected in mammalian cells.

Plant chloroplast thylakoid membranes however, have unique lipid composition as they are deficient in phospholipids. Also, their largest constituent, monogalactosyl diglyceride or MGDG, does not form aqueous bilayers. Nevertheless, dynamic studies reveal a normal lipid bilayer organisation in thylakoid membranes. [9]

Experimental techniques

Lipid extraction

Most methods of lipid extraction and isolation from biological samples exploit the high solubility of hydrocarbon chains in organic solvents. Given the diversity in lipid classes, it is not possible to accommodate all classes with a common extraction method. The traditional Bligh/Dyer procedure [10] uses chloroform/methanol-based protocols that include phase partitioning into the organic layer. However, several protocols now exist, with newer methods overcoming the shortcomings of older ones and solving problems associated with, for example, targeted lipid isolation or high throughput data collection [11] . Most protocols work relatively well for a variety of physiologically relevant lipids but they have to be adapted for species with particular properties and low-abundance and labile lipid metabolites [12] [13] [14] [15] [16] [17] .

Lipid separation

The simplest method of lipid separation is the use of thin layer chromatography (TLC). Although not as sensitive as other methods of lipid detection, it offers a rapid and comprehensive screening tool prior to more sensitive and sophisticated techniques. Solid-phase extraction (SPE) chromatography is useful for rapid, preparative separation of crude lipid mixtures into different lipid classes. This involves the use of prepacked columns containing silica or other stationary phases to separate glycerophospholipids, fatty acids, cholesteryl esters, glycerolipids, and sterols from crude lipid mixtures. [18] High-performance liquid chromatography (HPLC or LC) is extensively used in lipidomic analysis to separate lipids prior to mass analysis. Separation can be achieved by either normal-phase (NP) HPLC or reverse-phase (RP) HPLC. For example, NP-HPLC effectively separates glycerophospholipids on the basis of headgroup polarity, [19] whereas RP-HPLC effectively separates fatty acids such as eicosanoids on the basis of chain length, degree of unsaturation and substitution. [20] For global, untargeted lipidomic studies it is common to use both RP and NP or Hydrophilic Interaction Liquid Chromatrography (HILC) columns for increased lipidome coverage. The application of nano-flow liquid chromatography (nLC) proved thereby to be most efficient to enhance both general measurement sensitivity and lipidome coverage for a global lipidomics approach. [21] Chromatographic (HPLC/UHPLC) separation of lipids may either be performed offline or online where the eluate is integrated with the ionization source of a mass spectrometer.

Lipid detection

The progress of modern lipidomics has been greatly accelerated by the development of spectrometric methods in general and soft ionization techniques for mass spectrometry such as electrospray ionization (ESI), [5] desorption electrospray ionization (DESI), [22] and matrix-assisted laser desorption/ionization (MALDI) [23] in particular. "Soft" ionization does not cause extensive fragmentation, so that comprehensive detection of an entire range of lipids within a complex mixture can be correlated to experimental conditions or disease state. In addition, the technique of atmospheric pressure chemical ionization (APCI) has become increasingly popular for the analysis of nonpolar lipids. [24]

Schema showing detection of a fatty acid by LC-MS/MS using a linear ion-trap instrument and an electrospray (ESI) ion source. Tandem ms.png
Schema showing detection of a fatty acid by LC-MS/MS using a linear ion-trap instrument and an electrospray (ESI) ion source.

ESI MS

ESI-MS was initially developed by Fenn and colleagues for analysis of biomolecules. [25] It depends on the formation of gaseous ions from polar, thermally labile and mostly non-volatile molecules and thus is completely suitable for a variety of lipids. It is a soft-ionization method that rarely disrupts the chemical nature of the analyte prior to mass analysis. Various ESI-MS methods have been developed for analysis of different classes, subclasses, and individual lipid species from biological extracts. Comprehensive reviews of the methods and their application have recently been published. [26] The major advantages of ESI-MS are high accuracy, sensitivity, reproducibility, and the applicability of the technique to complex solutions without prior derivatization. Han and coworkers have developed a method known as"shotgun lipidomics" which involves direct infusion of a crude lipid extract into an ESI source optimized for intrasource separation of lipids based on their intrinsic electrical properties. [27]

DESI MS

DESI mass spectrometry is an ambient ionization technique developed by Professor Zoltan Takáts, et al., in Professor Graham Cooks' group from Purdue University. [22] It combines the ESI and desorption ionization techniques, by directing an electrically charged mist to the sample surface that is a few millimeters away. [28] The technique has been successfully applied to lipidomics as imaging tool to map the lipid distributions within tissue specimens. [29] One of the advantages of DESI MS is that no matrix is required for tissue preparation, allowing multiple consecutive measurements on the same tissue specimen. DESI MS can also be used for imaging of lipids from tissue sections. [30]

MALDI MS

MALDI mass spectrometry is a laser-based soft-ionization method often used for analysis of large proteins, but has been used successfully for lipids. The lipid is mixed with a matrix, such as 2,5-dihydroxybenzoic acid, and applied to a sample holder as a small spot. A laser is fired at the spot, and the matrix absorbs the energy, which is then transferred to the analyte, resulting in ionization of the molecule. MALDI-Time-of-flight (MALDI-TOF) MS has become a very promising approach for lipidomics studies, particularly for the imaging of lipids from tissue slides. [31]

APCI MS

The source for APCI is similar to ESI except that ions are formed by the interaction of the heated analyte solvent with a corona discharge needle set at a high electrical potential. Primary ions are formed immediately surrounding the needle, and these interact with the solvent to form secondary ions that ultimately ionize the sample. APCI is particularly useful for the analysis of nonpolar lipids such as triacylglycerols, sterols, and fatty acid esters. [32]

Imaging techniques

The high sensitivity of DESI in the lipid range makes it a powerful technique for the detection and mapping of lipids abundances within tissue specimens. [33] Recent developments in MALDI methods have enabled direct detection of lipids in-situ. Abundant lipid-related ions are produced from the direct analysis of thin tissue slices when sequential spectra are acquired across a tissue surface that has been coated with a MALDI matrix. Collisional activation of the molecular ions can be used to determine the lipid family and often structurally define the molecular species. These techniques enable detection of phospholipids, sphingolipids and glycerolipids in tissues such as heart, kidney and brain. Furthermore, distribution of many different lipid molecular species often define anatomical regions within these tissues. [34] [35]

Lipid profiling

Quantitative lipid profiles (lipidomes) of yeast Saccharomyces cerevisiae grown in different temperatures Flexibility of a eukaryotic lipidome - insights from yeast lipidomics-Klose, Surma 2012 fig2.svg
Quantitative lipid profiles (lipidomes) of yeast Saccharomyces cerevisiae grown in different temperatures

Lipid profiling is a targeted metabolomics platform that provides a comprehensive analysis of lipid species within a cell or tissue. Profiling based on electrospray ionization tandem mass spectrometry (ESI-MS/MS) is capable of providing quantitative data and is adaptable to high throughput analyses. [37] The powerful approach of transgenics, namely deletion and/or overexpression of a gene product coupled with lipidomics, can give valuable insights into the role of biochemical pathways. [38] Lipid profiling techniques have also been applied to plants [39] and microorganisms such as yeast. [36] [40] [21] A combination of quantitative lipidomic data in conjunction with the corresponding transcriptional data (using gene-array methods) and proteomic data (using tandem MS) enables a systems biology approach to a more in-depth understanding of the metabolic or signaling pathways of interest.

Informatics

A major challenge for lipidomics, in particular for MS-based approaches, lies in the computational and bioinformatic demands of handling the large amount of data that arise at various stages along the chain of information acquisition and processing. [41] [42] Chromatographic and MS data collection requires substantial efforts in spectral alignment and statistical evaluation of fluctuations in signal intensities. Such variations have a multitude of origins, including biological variations, sample handling and analytical accuracy. As a consequence several replicates are normally required for reliable determination of lipid levels in complex mixtures. Within the last few years, a number of software packages have been developed by various companies and research groups to analyze data generated by MS profiling of metabolites, including lipids. The data processing for differential profiling usually proceed through several stages, including input file manipulation, spectral filtering, peak detection, chromatographic alignment, normalization, visualization, and data export. An example of metabolic profiling software is the freely-available Java-based Mzmine application. [43] Another is Metabolon, Inc’s commercial applications for metabolomic analysis using proprietary software. [44] Recently MS-DIAL 4 software was integrated with a comprehensive lipidome atlas with retention time, collision cross-section and tandem mass spectrometry information for 117 lipid subclasses and 8,051 lipids. [45] Some software packages such as Markerview [46] include multivariate statistical analysis (for example, principal component analysis) and these will be helpful for the identification of correlations in lipid metabolites that are associated with a physiological phenotype, in particular for the development of lipid-based biomarkers. Another objective of the information technology side of lipidomics involves the construction of metabolic maps from data on lipid structures and lipid-related protein and genes. Some of these lipid pathways [47] are extremely complex, for example the mammalian glycosphingolipid pathway. [48] The establishment of searchable and interactive databases [49] [50] of lipids and lipid-related genes/proteins is also an extremely important resource as a reference for the lipidomics community. Integration of these databases with MS and other experimental data, as well as with metabolic networks [51] offers an opportunity to devise therapeutic strategies to prevent or reverse these pathological states involving dysfunction of lipid-related processes.

Related Research Articles

<span class="mw-page-title-main">Electrospray ionization</span> Technique used in mass spectroscopy

Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. ESI is different from other ionization processes since it may produce multiple-charged ions, effectively extending the mass range of the analyser to accommodate the kDa-MDa orders of magnitude observed in proteins and their associated polypeptide fragments.

<span class="mw-page-title-main">Matrix-assisted laser desorption/ionization</span> Ionization technique

In mass spectrometry, matrix-assisted laser desorption/ionization (MALDI) is an ionization technique that uses a laser energy-absorbing matrix to create ions from large molecules with minimal fragmentation. It has been applied to the analysis of biomolecules and various organic molecules, which tend to be fragile and fragment when ionized by more conventional ionization methods. It is similar in character to electrospray ionization (ESI) in that both techniques are relatively soft ways of obtaining ions of large molecules in the gas phase, though MALDI typically produces far fewer multi-charged ions.

<span class="mw-page-title-main">Liquid chromatography–mass spectrometry</span> Analytical chemistry technique

Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). Coupled chromatography – MS systems are popular in chemical analysis because the individual capabilities of each technique are enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides spectral information that may help to identify each separated component. MS is not only sensitive, but provides selective detection, relieving the need for complete chromatographic separation. LC–MS is also appropriate for metabolomics because of its good coverage of a wide range of chemicals. This tandem technique can be used to analyze biochemical, organic, and inorganic compounds commonly found in complex samples of environmental and biological origin. Therefore, LC–MS may be applied in a wide range of sectors including biotechnology, environment monitoring, food processing, and pharmaceutical, agrochemical, and cosmetic industries. Since the early 2000s, LC–MS has also begun to be used in clinical applications.

In lipidomics, the process of shotgun lipidomics uses analytical chemistry to investigate the biological function, significance, and sequelae of alterations in lipids and protein constituents mediating lipid metabolism, trafficking, or biological function in cells. Lipidomics has been greatly facilitated by recent advances in, and novel applications of, electrospray ionization mass spectrometry (ESI/MS).

<span class="mw-page-title-main">MALDI imaging</span> Imaging system

MALDI mass spectrometry imaging (MALDI-MSI) is the use of matrix-assisted laser desorption ionization as a mass spectrometry imaging technique in which the sample, often a thin tissue section, is moved in two dimensions while the mass spectrum is recorded. Advantages, like measuring the distribution of a large amount of analytes at one time without destroying the sample, make it a useful method in tissue-based study.

<span class="mw-page-title-main">Protein mass spectrometry</span> Application of mass spectrometry

Protein mass spectrometry refers to the application of mass spectrometry to the study of proteins. Mass spectrometry is an important method for the accurate mass determination and characterization of proteins, and a variety of methods and instrumentations have been developed for its many uses. Its applications include the identification of proteins and their post-translational modifications, the elucidation of protein complexes, their subunits and functional interactions, as well as the global measurement of proteins in proteomics. It can also be used to localize proteins to the various organelles, and determine the interactions between different proteins as well as with membrane lipids.

<span class="mw-page-title-main">Desorption electrospray ionization</span>

Desorption electrospray ionization (DESI) is an ambient ionization technique that can be coupled to mass spectrometry (MS) for chemical analysis of samples at atmospheric conditions. Coupled ionization sources-MS systems are popular in chemical analysis because the individual capabilities of various sources combined with different MS systems allow for chemical determinations of samples. DESI employs a fast-moving charged solvent stream, at an angle relative to the sample surface, to extract analytes from the surfaces and propel the secondary ions toward the mass analyzer. This tandem technique can be used to analyze forensics analyses, pharmaceuticals, plant tissues, fruits, intact biological tissues, enzyme-substrate complexes, metabolites and polymers. Therefore, DESI-MS may be applied in a wide variety of sectors including food and drug administration, pharmaceuticals, environmental monitoring, and biotechnology.

Mass spectrometry imaging (MSI) is a technique used in mass spectrometry to visualize the spatial distribution of molecules, as biomarkers, metabolites, peptides or proteins by their molecular masses. After collecting a mass spectrum at one spot, the sample is moved to reach another region, and so on, until the entire sample is scanned. By choosing a peak in the resulting spectra that corresponds to the compound of interest, the MS data is used to map its distribution across the sample. This results in pictures of the spatially resolved distribution of a compound pixel by pixel. Each data set contains a veritable gallery of pictures because any peak in each spectrum can be spatially mapped. Despite the fact that MSI has been generally considered a qualitative method, the signal generated by this technique is proportional to the relative abundance of the analyte. Therefore, quantification is possible, when its challenges are overcome. Although widely used traditional methodologies like radiochemistry and immunohistochemistry achieve the same goal as MSI, they are limited in their abilities to analyze multiple samples at once, and can prove to be lacking if researchers do not have prior knowledge of the samples being studied. Most common ionization technologies in the field of MSI are DESI imaging, MALDI imaging, secondary ion mass spectrometry imaging and Nanoscale SIMS (NanoSIMS).

Sample preparation for mass spectrometry is used for the optimization of a sample for analysis in a mass spectrometer (MS). Each ionization method has certain factors that must be considered for that method to be successful, such as volume, concentration, sample phase, and composition of the analyte solution. Quite possibly the most important consideration in sample preparation is knowing what phase the sample must be in for analysis to be successful. In some cases the analyte itself must be purified before entering the ion source. In other situations, the matrix, or everything in the solution surrounding the analyte, is the most important factor to consider and adjust. Often, sample preparation itself for mass spectrometry can be avoided by coupling mass spectrometry to a chromatography method, or some other form of separation before entering the mass spectrometer. In some cases, the analyte itself must be adjusted so that analysis is possible, such as in protein mass spectrometry, where usually the protein of interest is cleaved into peptides before analysis, either by in-gel digestion or by proteolysis in solution.

<span class="mw-page-title-main">Laser spray ionization</span>

Laser spray ionization refers to one of several methods for creating ions using a laser interacting with a spray of neutral particles or ablating material to create a plume of charged particles. The ions thus formed can be separated by m/z with mass spectrometry. Laser spray is one of several ion sources that can be coupled with liquid chromatography-mass spectrometry for the detection of larger molecules.

<span class="mw-page-title-main">Matrix-assisted laser desorption electrospray ionization</span>

Matrix-assisted laser desorption electrospray ionization (MALDESI) was first introduced in 2006 as a novel ambient ionization technique which combines the benefits of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). An infrared (IR) or ultraviolet (UV) laser can be utilized in MALDESI to resonantly excite an endogenous or exogenous matrix. The term 'matrix' refers to any molecule that is present in large excess and absorbs the energy of the laser, thus facilitating desorption of analyte molecules. The original MALDESI design was implemented using common organic matrices, similar to those used in MALDI, along with a UV laser. The current MALDESI source employs endogenous water or a thin layer of exogenously deposited ice as the energy-absorbing matrix where O-H symmetric and asymmetric stretching bonds are resonantly excited by a mid-IR laser.

<span class="mw-page-title-main">Desorption atmospheric pressure photoionization</span>

Desorption atmospheric pressure photoionization (DAPPI) is an ambient ionization technique for mass spectrometry that uses hot solvent vapor for desorption in conjunction with photoionization. Ambient Ionization techniques allow for direct analysis of samples without pretreatment. The direct analysis technique, such as DAPPI, eliminates the extraction steps seen in most nontraditional samples. DAPPI can be used to analyze bulkier samples, such as, tablets, powders, resins, plants, and tissues. The first step of this technique utilizes a jet of hot solvent vapor. The hot jet thermally desorbs the sample from a surface. The vaporized sample is then ionized by the vacuum ultraviolet light and consequently sampled into a mass spectrometer. DAPPI can detect a range of both polar and non-polar compounds, but is most sensitive when analyzing neutral or non-polar compounds. This technique also offers a selective and soft ionization for highly conjugated compounds.

<span class="mw-page-title-main">Capillary electrophoresis–mass spectrometry</span>

Capillary electrophoresis–mass spectrometry (CE–MS) is an analytical chemistry technique formed by the combination of the liquid separation process of capillary electrophoresis with mass spectrometry. CE–MS combines advantages of both CE and MS to provide high separation efficiency and molecular mass information in a single analysis. It has high resolving power and sensitivity, requires minimal volume and can analyze at high speed. Ions are typically formed by electrospray ionization, but they can also be formed by matrix-assisted laser desorption/ionization or other ionization techniques. It has applications in basic research in proteomics and quantitative analysis of biomolecules as well as in clinical medicine. Since its introduction in 1987, new developments and applications have made CE-MS a powerful separation and identification technique. Use of CE–MS has increased for protein and peptides analysis and other biomolecules. However, the development of online CE–MS is not without challenges. Understanding of CE, the interface setup, ionization technique and mass detection system is important to tackle problems while coupling capillary electrophoresis to mass spectrometry.

<span class="mw-page-title-main">Ambient ionization</span>

Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrometer without sample preparation or separation. Ions can be formed by extraction into charged electrospray droplets, thermally desorbed and ionized by chemical ionization, or laser desorbed or ablated and post-ionized before they enter the mass spectrometer.

<span class="mw-page-title-main">Instrumental chemistry</span> Study of analytes using scientific instruments

Instrumental analysis is a field of analytical chemistry that investigates analytes using scientific instruments.

<span class="mw-page-title-main">Laser ablation electrospray ionization</span>

Laser ablation electrospray ionization (LAESI) is an ambient ionization method for mass spectrometry that combines laser ablation from a mid-infrared (mid-IR) laser with a secondary electrospray ionization (ESI) process. The mid-IR laser is used to generate gas phase particles which are then ionized through interactions with charged droplets from the ESI source. LAESI was developed in Professor Akos Vertes lab by Peter Nemes in 2007 and it was marketed commercially by Protea Biosciences, Inc until 2017. Fiber-LAESI for single-cell analysis approach was developed by Bindesh Shrestha in Professor Vertes lab in 2009. LAESI is a novel ionization source for mass spectrometry (MS) that has been used to perform MS imaging of plants, tissues, cell pellets, and even single cells. In addition, LAESI has been used to analyze historic documents and untreated biofluids such as urine and blood. The technique of LAESI is performed at atmospheric pressure and therefore overcomes many of the obstacles of traditional MS techniques, including extensive and invasive sample preparation steps and the use of high vacuum. Because molecules and aerosols are ionized by interacting with an electrospray plume, LAESI's ionization mechanism is similar to SESI and EESI techniques.

<span class="mw-page-title-main">Matrix-assisted ionization</span>

In mass spectrometry, matrix-assisted ionization is a low fragmentation (soft) ionization technique which involves the transfer of particles of the analyte and matrix sample from atmospheric pressure (AP) to the heated inlet tube connecting the AP region to the vacuum of the mass analyzer.

<span class="mw-page-title-main">MasSpec Pen</span>

The MasSpec Pen, or the precìso MasSpec Pen System, is a mass spectrometry (MS) based cancer detection and diagnosis system that can be used for ex vivo and in vivo tissue sample analysis. The system collects biological molecules from a tissue sample surface via a solid-liquid extraction mechanism and transports the molecules to a mass spectrometer for analysis. The composition of the extracted molecules can then be used to predict if the tissue sample analyzed contains cancerous cells using machine learning algorithms and statistical models. In early-stage clinical research, the MasSpec Pen system was able to distinguish various cancer tissues, including thyroid, breast, lung, and ovarian tumor tissues, from their normal counterparts with an overall accuracy of 96.3%. A follow-up study in illustrating the use of the device for detection of serous ovarian carcinoma in ex vivo tissue biopsies allowed for the discrimination of normal and cancerous ovarian samples with a clinical sensitivity and specificity of 94.0% and 94.4%, respectively.

Barbara Seliger Larsen is a mass spectrometrist, with a career in instrumentations and applications of mass spectrometry in industry, and served on the board of the American Society for Mass Spectrometry for several terms.

References

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  5. 1 2 Han X, Gross RW; Gross (June 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 (6): 1071–9. doi: 10.1194/jlr.R300004-JLR200 . PMID   12671038.
  6. ↑ LIPID MAPS Consortium
  7. ↑ European Lipidomics Initiative
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  11. ↑ Furse S, Egmond MR, Killian, JA; Egmond; Killian (2015). "Isolation of lipids from biological samples". Mol Membr Biol. 32 (3): 55–64. doi:10.3109/09687688.2015.1050468. hdl:1874/329957. PMID   26212444. S2CID   24537585.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  13. ↑ Ivanova PT, Milne SB, Byrne MO, Xiang Y, Brown HA; Milne; Byrne; Xiang; Brown (2007). "Glycerophospholipid Identification and Quantitation by Electrospray Ionization Mass Spectrometry". Lipidomics and Bioactive Lipids: Mass-Spectrometry–Based Lipid Analysis. Methods in Enzymology. Vol. 432. pp. 21–57. doi:10.1016/S0076-6879(07)32002-8. ISBN   978-0-12-373895-0. PMID   17954212.{{cite book}}: CS1 maint: multiple names: authors list (link)
  14. ↑ Deems R, Buczynski MW, Bowers-Gentry R, Harkewicz R, Dennis EA; Buczynski; Bowers-Gentry; Harkewicz; Dennis (2007). "Detection and Quantitation of Eicosanoids via High Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry". Lipidomics and Bioactive Lipids: Mass-Spectrometry–Based Lipid Analysis. Methods in Enzymology. Vol. 432. pp. 59–82. doi:10.1016/S0076-6879(07)32003-X. ISBN   978-0-12-373895-0. PMID   17954213. S2CID   37207815.{{cite book}}: CS1 maint: multiple names: authors list (link)
  15. ↑ McDonald JG, Thompson BM, McCrum EC, Russell DW; Thompson; McCrum; Russell (2007). "Extraction and Analysis of Sterols in Biological Matrices by High Performance Liquid Chromatography Electrospray Ionization Mass Spectrometry". Lipidomics and Bioactive Lipids: Mass-Spectrometry–Based Lipid Analysis. Methods in Enzymology. Vol. 432. pp. 145–70. doi:10.1016/S0076-6879(07)32006-5. ISBN   978-0-12-373895-0. PMID   17954216.{{cite book}}: CS1 maint: multiple names: authors list (link)
  16. ↑ Garrett TA, Guan Z, Raetz CR; Guan; Raetz (2007). "Analysis of Ubiquinones, Dolichols, and Dolichol Diphosphate-Oligosaccharides by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry". Lipidomics and Bioactive Lipids: Mass-Spectrometry–Based Lipid Analysis. Methods in Enzymology. Vol. 432. pp. 117–43. doi:10.1016/S0076-6879(07)32005-3. ISBN   978-0-12-373895-0. PMID   17954215.{{cite book}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Sullards MC, Allegood JC, Kelly S, Wang E, Haynes CA, Park H, Chen Y, Merrill AH; Allegood; Kelly; Wang; Haynes; Park; Chen; Merrill Jr (2007). "Structure-Specific, Quantitative Methods for Analysis of Sphingolipids by Liquid Chromatography–Tandem Mass Spectrometry: "Inside-Out" Sphingolipidomics". Lipidomics and Bioactive Lipids: Mass-Spectrometry–Based Lipid Analysis. Methods in Enzymology. Vol. 432. pp. 83–115. doi:10.1016/S0076-6879(07)32004-1. ISBN   978-0-12-373895-0. PMID   17954214.{{cite book}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Kaluzny MA, Duncan LA, Merritt MV, Epps DE; Duncan; Merritt; Epps (January 1985). "Rapid separation of lipid classes in high yield and purity using bonded phase columns". J. Lipid Res. 26 (1): 135–40. doi: 10.1016/S0022-2275(20)34412-6 . PMID   3973509.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  48. ↑ SphingoMAP
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