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A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language
Ronny Herzog, Dominik Schwudke, Kai Schuhmann, Julio L Sampaio, Stefan R Bornstein, Michael Schroeder, Andrej Shevchenko
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-1-r8
Abstract: Lipidomics, an emerging scientific discipline, aims at the quantitative molecular characterization of the full lipid complement of cells, tissues or whole organisms (reviewed in [1-4]). Eukaryotic lipidomes comprise over a hundred lipid classes, each of which is represented by a large number of individual yet structurally related molecules. According to different estimates, a eukaryotic lipidome might contain from 9,000 to 100,000 individual molecular lipid species in total [2,5]. Due to the enormous compositional complexity and diversity of physicochemical properties of individual lipid molecules, lipidomic analyses rely heavily on mass spectrometry. A shotgun lipidomics methodology implies that total lipid extracts from cells or tissues are directly infused into a tandem mass spectrometer and the identification of individual species relies on their accurately determined masses and/or MS/MS spectra acquired from corresponding precursor ions [6-8].The apparent technical simplicity of shotgun lipidomics is appealing; indeed, molecular species from many lipid classes are determined in parallel in a single analysis with no chromatographic separation required. Species quantification is simplified because in direct infusion experiments the composition of electrosprayed analytes does not change over time. Adjusting the solvent composition (organic phase content, basic or acidic pH, buffer concentration) and ionization conditions (polarity mode, declustering energy, interface temperature, etc.) enhances the detection sensitivity by several orders of magnitude [8,9]. In shotgun tandem mass spectrometry (MS/MS) analysis, all detectable precursors (or, alternatively, all plausible precursors from a pre-defined inclusion list) could be fragmented [10]. Given enough time, the shotgun analysis would ultimately produce a comprehensive dataset of MS and MS/MS spectra comprising all fragment ions obtained from all ionizable lipid precursors.While methods of acquiring shotgun mass s
Analysis of Lipid Experiments (ALEX): A Software Framework for Analysis of High-Resolution Shotgun Lipidomics Data  [PDF]
Peter Husen, Kirill Tarasov, Maciej Katafiasz, Elena Sokol, Johannes Vogt, Jan Baumgart, Robert Nitsch, Kim Ekroos, Christer S. Ejsing
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079736
Abstract: Global lipidomics analysis across large sample sizes produces high-content datasets that require dedicated software tools supporting lipid identification and quantification, efficient data management and lipidome visualization. Here we present a novel software-based platform for streamlined data processing, management and visualization of shotgun lipidomics data acquired using high-resolution Orbitrap mass spectrometry. The platform features the ALEX framework designed for automated identification and export of lipid species intensity directly from proprietary mass spectral data files, and an auxiliary workflow using database exploration tools for integration of sample information, computation of lipid abundance and lipidome visualization. A key feature of the platform is the organization of lipidomics data in ”database table format” which provides the user with an unsurpassed flexibility for rapid lipidome navigation using selected features within the dataset. To demonstrate the efficacy of the platform, we present a comparative neurolipidomics study of cerebellum, hippocampus and somatosensory barrel cortex (S1BF) from wild-type and knockout mice devoid of the putative lipid phosphate phosphatase PRG-1 (plasticity related gene-1). The presented framework is generic, extendable to processing and integration of other lipidomic data structures, can be interfaced with post-processing protocols supporting statistical testing and multivariate analysis, and can serve as an avenue for disseminating lipidomics data within the scientific community. The ALEX software is available at www.msLipidomics.info.
Shotgun Lipidomics by Sequential Precursor Ion Fragmentation on a Hybrid Quadrupole Time-of-Flight Mass Spectrometer  [PDF]
Brigitte Simons,Dimple Kauhanen,Tuulia Sylv?nne,Kirill Tarasov,Eva Duchoslav,Kim Ekroos
Metabolites , 2012, DOI: 10.3390/metabo2010195
Abstract: Shotgun lipidomics has evolved into a myriad of multi-dimensional strategies for molecular lipid characterization, including bioinformatics tools for mass spectrum interpretation and quantitative measurements to study systems-lipidomics in complex biological extracts. Taking advantage of spectral mass accuracy, scan speed and sensitivity of improved quadrupole linked time-of-flight mass analyzers, we developed a bias-free global lipid profiling acquisition technique of sequential precursor ion fragmentation called MS/MS ALL. This generic information-independent tandem mass spectrometry (MS) technique consists of a Q1 stepped mass isolation window through a set mass range in small increments, fragmenting and recording all product ions and neutral losses. Through the accurate MS and MS/MS information, the molecular lipid species are resolved, including distinction of isobaric and isomeric species, and composed into more precise lipidomic outputs. The method demonstrates good reproducibility and at least 3 orders of dynamic quantification range for isomeric ceramides in human plasma. More than 400 molecular lipids in human plasma were uncovered and quantified in less than 12 min, including acquisitions in both positive and negative polarity modes. We anticipate that the performance of sequential precursor ion fragmentation both in quality and throughput will lead to the uncovering of new avenues throughout the biomedical research community, enhance biomarker discovery and provide novel information target discovery programs as it will prospectively shed new insight into affected metabolic and signaling pathways.
Shotgun Lipidomics Identifies a Paired Rule for the Presence of Isomeric Ether Phospholipid Molecular Species  [PDF]
Kui Yang, Zhongdan Zhao, Richard W. Gross, Xianlin Han
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001368
Abstract: Background Ether phospholipids are abundant membrane constituents present in electrically active tissues (e.g., heart and the brain) that play important roles in cellular function. Alterations of ether phospholipid molecular species contents are associated with a number of genetic disorders and human diseases. Methodology/Principal Findings Herein, the power of shotgun lipidomics, in combination with high mass accuracy/high resolution mass spectrometry, was explored to identify a paired rule for the presence of isomeric ether phospholipid molecular species in cellular lipidomes. The rule predicts that if an ether phospholipid A′-B is present in a lipidome, its isomeric counterpart B′-A is also present (where the ′ represents an ether linkage). The biochemical basis of this rule results from the fact that the enzymes which participate in either the sequential oxidation of aliphatic alcohols to fatty acids, or the reduction of long chain fatty acids to aliphatic alcohols (metabolic precursors of ether lipid synthesis), are not entirely selective with respect to acyl chain length or degree of unsaturation. Moreover, the enzymatic selectivity for the incorporation of different aliphatic chains into the obligatory precursor of ether lipids (i.e., 1-O-alkyl-glycero-3-phosphate) is also limited. Conclusions/Significance This intrinsic amplification of the number of lipid molecular species present in biological membranes predicted by this rule and demonstrated in this study greatly expands the number of ether lipid molecular species present in cellular lipidomes. Application of this rule to mass spectrometric analyses provides predictive clues to the presence of specific molecular species and greatly expands the number of identifiable and quantifiable ether lipid species present in biological samples. Through appropriate alterations in the database, use of the paired rule increases the number of identifiable metabolites in metabolic networks, thereby facilitating identification of biomarkers presaging disease states.
Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using Metabolomics  [PDF]
Eugenia Trushina, Tumpa Dutta, Xuan-Mai T. Persson, Michelle M. Mielke, Ronald C. Petersen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063644
Abstract: Alzheimer’s Disease (AD) currently affects more than 5 million Americans, with numbers expected to grow dramatically as the population ages. The pathophysiological changes in AD patients begin decades before the onset of dementia, highlighting the urgent need for the development of early diagnostic methods. Compelling data demonstrate that increased levels of amyloid-beta compromise multiple cellular pathways; thus, the investigation of changes in various cellular networks is essential to advance our understanding of early disease mechanisms and to identify novel therapeutic targets. We applied a liquid chromatography/mass spectrometry-based non-targeted metabolomics approach to determine global metabolic changes in plasma and cerebrospinal fluid (CSF) from the same individuals with different AD severity. Metabolic profiling detected a total of significantly altered 342 plasma and 351 CSF metabolites, of which 22% were identified. Based on the changes of >150 metabolites, we found 23 altered canonical pathways in plasma and 20 in CSF in mild cognitive impairment (MCI) vs. cognitively normal (CN) individuals with a false discovery rate <0.05. The number of affected pathways increased with disease severity in both fluids. Lysine metabolism in plasma and the Krebs cycle in CSF were significantly affected in MCI vs. CN. Cholesterol and sphingolipids transport was altered in both CSF and plasma of AD vs. CN. Other 30 canonical pathways significantly disturbed in MCI and AD patients included energy metabolism, Krebs cycle, mitochondrial function, neurotransmitter and amino acid metabolism, and lipid biosynthesis. Pathways in plasma that discriminated between all groups included polyamine, lysine, tryptophan metabolism, and aminoacyl-tRNA biosynthesis; and in CSF involved cortisone and prostaglandin 2 biosynthesis and metabolism. Our data suggest metabolomics could advance our understanding of the early disease mechanisms shared in progression from CN to MCI and to AD.
The Profiling Method of Lipidomics and Its Applications
脂质组学研究方法及其应用

王涛,梅旭荣,钟秀丽,李玉中
植物学报 , 2010,
Abstract: Lipids provide both the structural basis of the cell membrane and fuel for metabolism. In plants, increasing evidence has demonstrated roles for lipids in cellular processes. As one of the most important branches of metabolomics, lipidomics may be a comprehensive strategy to study the cellular lipidomes and their biological roles in terms of protein expression and gene regulation involved in lipid metabolism and function. Progress in lipidomics has been driven by development in analytical methods and approaches. In recent years, with the increasing attention to and interest in lipidomics, great progress has been made in analytical strategies for lipidomics. Some advanced strategies to analyze lipid composition in animals have been successfully extended to plants. This review gives an overview of the current strategies in lipid profiling, to promote the development of lipidomics, especially plant lipidomics.
Quantitative Metabolomics by 1H-NMR and LC-MS/MS Confirms Altered Metabolic Pathways in Diabetes  [PDF]
Ian R. Lanza,Shucha Zhang,Lawrence E. Ward,Helen Karakelides,Daniel Raftery,K. Sreekumaran Nair
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010538
Abstract: Insulin is as a major postprandial hormone with profound effects on carbohydrate, fat, and protein metabolism. In the absence of exogenous insulin, patients with type 1 diabetes exhibit a variety of metabolic abnormalities including hyperglycemia, glycosurea, accelerated ketogenesis, and muscle wasting due to increased proteolysis. We analyzed plasma from type 1 diabetic (T1D) humans during insulin treatment (I+) and acute insulin deprivation (I-) and non-diabetic participants (ND) by 1H nuclear magnetic resonance spectroscopy and liquid chromatography-tandem mass spectrometry. The aim was to determine if this combination of analytical methods could provide information on metabolic pathways known to be altered by insulin deficiency. Multivariate statistics differentiated proton spectra from I- and I+ based on several derived plasma metabolites that were elevated during insulin deprivation (lactate, acetate, allantoin, ketones). Mass spectrometry revealed significant perturbations in levels of plasma amino acids and amino acid metabolites during insulin deprivation. Further analysis of metabolite levels measured by the two analytical techniques indicates several known metabolic pathways that are perturbed in T1D (I-) (protein synthesis and breakdown, gluconeogenesis, ketogenesis, amino acid oxidation, mitochondrial bioenergetics, and oxidative stress). This work demonstrates the promise of combining multiple analytical methods with advanced statistical methods in quantitative metabolomics research, which we have applied to the clinical situation of acute insulin deprivation in T1D to reflect the numerous metabolic pathways known to be affected by insulin deficiency.
Lipidomics of Glycosphingolipids  [PDF]
Hany Farwanah,Thomas Kolter
Metabolites , 2012, DOI: 10.3390/metabo2010134
Abstract: Glycosphingolipids (GSLs) contain one or more sugars that are attached to a sphingolipid moiety, usually to a ceramide, but in rare cases also to a sphingoid base. A large structural heterogeneity results from differences in number, identity, linkage, and anomeric configuration of the carbohydrate residues, and also from structural differences within the hydrophobic part. GSLs form complex cell-type specific patterns, which change with the species, the cellular differentiation state, viral transformation, ontogenesis, and oncogenesis. Although GSL structures can be assigned to only a few series with a common carbohydrate core, their structural variety and the complex pattern are challenges for their elucidation and quantification by mass spectrometric techniques. We present a general overview of the application of lipidomics for GSL determination. This includes analytical procedures and instrumentation together with recent correlations of GSL molecular species with human diseases. Difficulties such as the structural complexity and the lack of standard substances for complex GSLs are discussed.
Flexibility of a Eukaryotic Lipidome – Insights from Yeast Lipidomics  [PDF]
Christian Klose, Michal A. Surma, Mathias J. Gerl, Felix Meyenhofer, Andrej Shevchenko, Kai Simons
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035063
Abstract: Mass spectrometry-based shotgun lipidomics has enabled the quantitative and comprehensive assessment of cellular lipid compositions. The yeast Saccharomyces cerevisiae has proven to be a particularly valuable experimental system for studying lipid-related cellular processes. Here, by applying our shotgun lipidomics platform, we investigated the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids. This extensive dataset allowed for a quantitative description of the intrinsic flexibility of a eukaryotic lipidome, thereby providing new insights into the adjustments of lipid biosynthetic pathways. In addition, we established a baseline for future lipidomic experiments in yeast. Finally, flexibility of lipidomic features is proposed as a new parameter for the description of the physiological state of an organism.
Altered proteolytic events in experimental autoimmune encephalomyelitis discovered by iTRAQ shotgun proteomics analysis of spinal cord
Mohit Jain, Shengjie Bian, Tong Liu, Jun Hu, Stella Elkabes, Hong Li
Proteome Science , 2009, DOI: 10.1186/1477-5956-7-25
Abstract: We discovered that several proteins, such as α1-macroglobulin, a protease inhibitor, α1B-glycoprotein, β2-microglobulin, neurofilament light polypeptide and sulfated glycoprotein 1 had non-tryptic peptide iTRAQ ratios that were substantially different from the overall protein iTRAQ ratios, suggesting that such peptides may be markers for the proteolytic products generated by the protease(s) altered during EAE. Indeed, subsequent Western blotting confirmed the dysregulation of specific protein cleavages in EAE tissues. Additional proteolytic changes in α2-macroglobulin, another protease inhibitor similar to α1-macroglobulin was also observed.The results from this study revealed changes among both neuronal protein processing and endogenous proteolysis modulators in EAE animals. This information may provide a rationale for protease inhibitor-based therapeutic interventions for multiple sclerosis.Proteases and peptidases are important regulators that govern many cellular functions [1]. Some protease activities are manifested globally, e.g. during protein turnover in lysosomes and proteasomes. Other proteases are activated only within particular defined contexts, serving specific signal transduction and other regulatory functions. Well-known examples include the caspase cascade during apoptosis, the coagulation cascade during clot formation and the classical and alternative complement innate immune systems for pathogen clearance. More recently, regulated proteolysis events have been implicated in numerous disease-related processes, including calpain activation following excitotoxicity in neuronal cells [2], matrix metalloprotease (MMP) modulation during cancer metastasis and multiple sclerosis [3], and the contribution of rennin and angiotensin converting enzyme to regulate blood pressure and cardiovascular function [4]. Understanding how protease activities are regulated is important both for discerning basic biological mechanisms and for developing therapies that can r
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