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• W2045790812 abstract "Lipoproteins are centrally important in lipid transport, fuel metabolism, and cardiovascular disease. The prototypic lipoprotein has an outer shell of amphipathic lipids and proteins that solubilizes a hydrophobic lipid core. Lipoprotein-associated proteins have classically been viewed as structural elements and factors important in lipid metabolism. Recent mass spectrometric analyses reveal that the protein cargo of lipoproteins is much more diverse than previously appreciated, raising the possibility that lipoproteins play previously unsuspected roles in host defense mechanisms and inflammation. They further suggest that lipoprotein-associated proteins can identify humans at increased risk of cardiovascular disease. Here, we summarize recent developments in lipoproteomics, the proteomic analysis of lipoproteins. We also discuss the promises and challenges this powerful analytical strategy offers for expanding our understanding of the biology and structures of lipoproteins. Lipoproteins are centrally important in lipid transport, fuel metabolism, and cardiovascular disease. The prototypic lipoprotein has an outer shell of amphipathic lipids and proteins that solubilizes a hydrophobic lipid core. Lipoprotein-associated proteins have classically been viewed as structural elements and factors important in lipid metabolism. Recent mass spectrometric analyses reveal that the protein cargo of lipoproteins is much more diverse than previously appreciated, raising the possibility that lipoproteins play previously unsuspected roles in host defense mechanisms and inflammation. They further suggest that lipoprotein-associated proteins can identify humans at increased risk of cardiovascular disease. Here, we summarize recent developments in lipoproteomics, the proteomic analysis of lipoproteins. We also discuss the promises and challenges this powerful analytical strategy offers for expanding our understanding of the biology and structures of lipoproteins. Lipoproteins play a central role in extracellular lipid transport in species ranging from insects to mammals (1Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4288) Google Scholar, 2Liu H. Ryan R.O. Role of lipid transfer particle in transformation of lipophorin in insect oocytes.Biochim. Biophys. Acta. 1991; 1085: 112-118Crossref PubMed Scopus (26) Google Scholar, 3Rader D.J. Molecular regulation of HDL metabolism and function: implications for novel therapies.J. Clin. Invest. 2006; 116: 3090-3100Crossref PubMed Scopus (464) Google Scholar). As couriers of lipids, they transport triglycerides derived from the diet to peripheral tissues for energy metabolism. They also are important for the bidirectional movement of cholesterol between the liver and peripheral tissues. However, lipoproteins are implicated in pathways distinct from lipid metabolism. For example, inflammation markedly alters lipoprotein metabolism (4Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar), and recent studies implicate lipoproteins as important mediators of the immune response and host defense mechanisms (5Chait A. Han C.Y. Oram J.F. Heinecke J.W. Thematic review series: the immune system and atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?.J. Lipid Res. 2005; 46: 389-403Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 6Getz G.S. Thematic review series: the immune system and atherogenesis. Bridging the innate and adaptive immune systems.J. Lipid Res. 2005; 46: 619-622Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Lipoproteins have attracted wide interest clinically because they are major risk factors for cardiovascular disease (CVD) in humans. For example, high levels of LDL cholesterol are a major risk factor for myocardial infarction and sudden death (7Anderson K.M. Odell P.M. Wilson P.W. Kannel W.B. Cardiovascular disease risk profiles.Am. Heart J. 1991; 121: 293-298Crossref PubMed Scopus (1737) Google Scholar). In contrast, low levels of HDL cholesterol strongly associate with an increased risk of CVD (8Gordon D.J. Rifkind B.M. High-density lipoprotein–the clinical implications of recent studies.N. Engl. J. Med. 1989; 321: 1311-1316Crossref PubMed Scopus (1397) Google Scholar), whereas high levels associate with longevity (9Barzilai N. Atzmon G. Schechter C. Schaefer E.J. Cupples A.L. Lipton R. Cheng S. Shuldiner A.R. Unique lipoprotein phenotype and genotype associated with exceptional longevity.JAMA. 2003; 290: 2030-2040Crossref PubMed Scopus (475) Google Scholar). LDL and HDL are the major carriers of cholesterol in plasma and serum, accounting for the strong relationship between cholesterol levels and CVD. Apolipoprotein (apo)B-100 is the major protein structural component of VLDL and LDL, whereas apoA-I serves that function in HDL. Chylomicrons contain apoB-48, a truncated form of apoB-100. Clinical studies suggest that levels of apoB-100 and apoA-I may be better predictors of CVD risk than LDL and HDL cholesterol levels (10Walldius G. Jungner I. Holme I. Aastveit A.H. Kolar W. Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study.Lancet. 2001; 358: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (1037) Google Scholar). Other protein components of LDL and HDL play important roles in lipid metabolism, energy homeostasis, and inflammation. Most studies of lipoproteins have focused on single proteins. Proteomics, a global approach to understanding protein expression, regulation, and function, transcends analysis of individual components. One of its major tools is mass spectrometry (MS) (11Aebersold R. Mann M. Mass spectrometry-based proteomics.Nature. 2003; 422: 198-207Crossref PubMed Scopus (5484) Google Scholar, 12Cravatt B.F. Simon G.M. Yates 3rd., J.R. The biological impact of mass-spectrometry-based proteomics.Nature. 2007; 450: 991-1000Crossref PubMed Scopus (554) Google Scholar), which can detect and quantify hundreds or even thousands of proteins in one sample. MS measures molecular mass and therefore can also detect and characterize posttranslational modifications of proteins (13Cantin G.T. Yates 3rd., J.R. Strategies for shotgun identification of post-translational modifications by mass spectrometry.J. Chromatogr. A. 2004; 1053: 7-14Crossref PubMed Scopus (77) Google Scholar). Its ability to identify disease-related biomarkers is also a powerful advantage (14Heinecke J.W. A “new” thematic series: mass spectrometry-based proteomics of lipid biology.J. Lipid Res. 2009; 50: 777-780Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Recent mass spectrometric studies have revealed that lipoproteins carry a diverse array of previously unsuspected proteins. For example, shotgun proteomics has implicated regulation of the complement pathway and proteolysis in HDL's cardioprotective effects (15Vaisar T. Pennathur S. Green P.S. Gharib S.A. Hoofnagle A.N. Cheung M.C. Byun J. Vuletic S. Kassim S. Singh P. et al.Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.J. Clin. Invest. 2007; 117: 746-756Crossref PubMed Scopus (772) Google Scholar). This review highlights lipoproteomics, using MS to study lipoprotein-associated proteins and their biology. We first provide brief overviews of lipoprotein physiology and MS. Then we summarize lipoproteomic studies, focusing on recent insights they have provided into lipoprotein function and biology. We also discuss the limitations of our current approaches as well as important technical and conceptual issues that should be addressed in future studies. Lipoproteins are classically considered to be spherical particles containing a hydrophobic core of neutral lipid (cholesteryl ester and triglycerides) and a surface rich in amphipathic proteins, phospholipids, and free cholesterol (1Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4288) Google Scholar, 2Liu H. Ryan R.O. Role of lipid transfer particle in transformation of lipophorin in insect oocytes.Biochim. Biophys. Acta. 1991; 1085: 112-118Crossref PubMed Scopus (26) Google Scholar, 3Rader D.J. Molecular regulation of HDL metabolism and function: implications for novel therapies.J. Clin. Invest. 2006; 116: 3090-3100Crossref PubMed Scopus (464) Google Scholar, 16Rader D.J. Hobbs H.H. Disorders of Lipoprotein Metabolism.in: Fauci A.S. Kasper D.L. Longo D.L. Braunwald E. Hauser S.L. Jameson J.L. Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill, New York2008: 2416-2429Google Scholar). These surface components solubilize the hydrophobic lipid core. In mammals, including humans, there are two major classes of lipoproteins: those containing apoB (chylomicrons, LDL, VLDL) and those containing apoA-I (HDL). The metabolism of each lipoprotein class is dictated by its major structural protein (16Rader D.J. Hobbs H.H. Disorders of Lipoprotein Metabolism.in: Fauci A.S. Kasper D.L. Longo D.L. Braunwald E. Hauser S.L. Jameson J.L. Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill, New York2008: 2416-2429Google Scholar). For instance, apoB-100 is required for binding LDL to the LDL receptor, which plays the essential role in uptake of LDL from the circulation by peripheral cells and the liver (1Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4288) Google Scholar). In contrast, the truncated form of apoB (apoB-48) present in chylomicrons lacks the LDL binding domain. Thus, remnant particles derived from chylomicrons by lipolysis of core lipids are cleared from the liver by pathways distinct from that of the LDL receptor. Enterocytes, which line the small intestine, assemble chylomicrons from triglycerides, phospholipids, and cholesterol derived from the diet and then secrete the nascent lipoprotein into the blood (Fig. 1). Chylomicrons are the largest lipoproteins in humans (16Rader D.J. Hobbs H.H. Disorders of Lipoprotein Metabolism.in: Fauci A.S. Kasper D.L. Longo D.L. Braunwald E. Hauser S.L. Jameson J.L. Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill, New York2008: 2416-2429Google Scholar). Together with VLDL, which is synthesized by the liver, these triglyceride-rich lipoproteins undergo lipolysis in muscle and adipose tissue to provide fatty acids for energy metabolism. ApoB-48 and apoB-100 serve as structural supports for chylomicrons and VLDL, respectively, permitting the formation of a large, hydrophobic core (17Schonfeld G. Familial hypobetalipoproteinemia: a review.J. Lipid Res. 2003; 44: 878-883Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). ApoC-II, another protein carried by triglyceride-rich lipoproteins that contain apoB, is a cofactor for lipoprotein lipase, which hydrolyzes triglycerides in the particles to free fatty acids (18Fojo S.S. Brewer H.B. Hypertriglyceridemia due to genetic-defects in lipoprotein-lipase and apolipoprotein-C-II.J. Intern. Med. 1992; 231: 669-677Crossref PubMed Scopus (100) Google Scholar). Deficiency of either protein results in profound disturbances in lipid metabolism, demonstrating the pivotal role apolipoproteins play in lipoprotein physiology. In contrast to the triglyceride-rich chylomicrons and VLDL particles, the major lipids in HDL and LDL are cholesterol and cholesteryl esters (3Rader D.J. Molecular regulation of HDL metabolism and function: implications for novel therapies.J. Clin. Invest. 2006; 116: 3090-3100Crossref PubMed Scopus (464) Google Scholar). LDL is largely derived from circulating VLDL by the action of lipases on triglycerides (18Fojo S.S. Brewer H.B. Hypertriglyceridemia due to genetic-defects in lipoprotein-lipase and apolipoprotein-C-II.J. Intern. Med. 1992; 231: 669-677Crossref PubMed Scopus (100) Google Scholar). ApoB-100 provides structural support for VLDL and LDL (17Schonfeld G. Familial hypobetalipoproteinemia: a review.J. Lipid Res. 2003; 44: 878-883Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). It also is the ligand for the LDL receptor on liver and peripheral tissue (1Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4288) Google Scholar, 19Brown M.S. Goldstein J.L. The receptor model for transport of cholesterol in plasma.Ann. N. Y. Acad. Sci. 1985; 454: 178-182Crossref PubMed Scopus (29) Google Scholar). Modified forms of apoB-containing particles, such as oxidized LDL, promote the conversion of artery wall macrophages into cholesteryl ester-laden foam cells, the hallmark of the atherosclerotic lesion (20Gaut J.P. Heinecke J.W. Mechanisms for oxidizing low-density lipoprotein. Insights from patterns of oxidation products in the artery wall and from mouse models of atherosclerosis.Trends Cardiovasc. Med. 2001; 11: 103-112Crossref PubMed Scopus (91) Google Scholar). ApoA-I functions as the scaffold for HDL assembly (21Davidson W.S. Thompson T.B. The structure of apolipoprotein A-I in high density lipoproteins.J. Biol. Chem. 2007; 282: 22249-22253Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Unlike apoB, apoA-I is associated with very little lipid when it is secreted from hepatocytes and enterocytes. In this poorly lipidated state, it serves as the ligand for ABCA1, which exports phospholipid and cholesterol into nascent HDL particles, promoting their maturation (22Oram J.F. Vaughan A.M. ATP-binding cassette cholesterol transporters and cardiovascular disease.Circ. Res. 2006; 99: 1031-1043Crossref PubMed Scopus (321) Google Scholar, 23Tall A.R. Yvan-Charvet L. Terasaka N. Pagler T. Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.Cell Metab. 2008; 7: 365-375Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar). HDL is protein-rich compared with other lipoproteins and contains many other apolipoproteins. Its apolipoproteins, in concert with other proteins like phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP), collaborate with apoA-I to orchestrate the exchange of lipids between lipoprotein particles (24Bruce C. Chouinard Jr., R.A. Tall A.R. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport.Annu. Rev. Nutr. 1998; 18: 297-330Crossref PubMed Scopus (229) Google Scholar). ApoA-I also has a central role in removing cholesterol from macrophage foam cells, making a key contribution to the cardioprotective effects of HDL (25Oram J.F. Heinecke J.W. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease.Physiol. Rev. 2005; 85: 1343-1372Crossref PubMed Scopus (414) Google Scholar). Apolipoproteins are often classified as nonexchangeable and exchangeable and each class has distinct structural features. ApoB exhibits both amphipathic α-helical and β-pleated sheet structure (26Segrest J.P. Jones M.K. De Loof H. Dashti N. Structure of apolipoprotein B-100 in low density lipoproteins.J. Lipid Res. 2001; 42: 1346-1367Abstract Full Text Full Text PDF PubMed Google Scholar). Each chylomicron, VLDL, or LDL particle contains 1 mol of apoB, which is not exchanged between different particles. In contrast, apoA-I exists largely as an amphipathic α-helical protein (21Davidson W.S. Thompson T.B. The structure of apolipoprotein A-I in high density lipoproteins.J. Biol. Chem. 2007; 282: 22249-22253Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Each circulating HDL particle contains 2–4 mol of apoA-I that can move between lipoprotein particles. A wide variety of other apolipoproteins (apoCs, apoE, etc.) are found on lipoproteins containing apoB and apoA-I, though in smaller amounts than in the major structural proteins. Lipoproteins also contain low-abundance proteins that generally do not exhibit the typical structural features of apolipoproteins. Certain of these, such as PLTP, CETP, and LCAT, have important roles in lipid metabolism. However, over the past decade, there has been an explosion of interest in minor protein components of lipoproteins that have functions distinct from lipid metabolism. For example, paraoxonase and clusterin, which are cotransported with HDL in plasma, have been proposed to have antioxidant and anti-inflammatory properties (4Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar, 5Chait A. Han C.Y. Oram J.F. Heinecke J.W. Thematic review series: the immune system and atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?.J. Lipid Res. 2005; 46: 389-403Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 27Barter P.J. Nicholls S. Rye K.A. Anantharamaiah G.M. Navab M. Fogelman A.M. Antiinflammatory properties of HDL.Circ. Res. 2004; 95: 764-772Crossref PubMed Scopus (1029) Google Scholar, 28Kontush A. Chapman M.J. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis.Pharmacol. Rev. 2006; 58: 342-374Crossref PubMed Scopus (601) Google Scholar). Importantly, levels of these proteins are markedly altered in humans with CVD and in mice that are susceptible to atherosclerosis (27Barter P.J. Nicholls S. Rye K.A. Anantharamaiah G.M. Navab M. Fogelman A.M. Antiinflammatory properties of HDL.Circ. Res. 2004; 95: 764-772Crossref PubMed Scopus (1029) Google Scholar, 28Kontush A. Chapman M.J. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis.Pharmacol. Rev. 2006; 58: 342-374Crossref PubMed Scopus (601) Google Scholar). Loss of anti-inflammatory and antioxidant proteins, perhaps in concert with gain of proinflammatory proteins, may thus be another key contributor to the antiatherogenic effects of HDL. There are three general approaches to identifying proteins in complex mixtures (reviewed in Refs. 29Gorg A. Weiss W. Dunn M.J. Current two-dimensional electrophoresis technology for proteomics.Proteomics. 2004; 4: 3665-3685Crossref PubMed Scopus (1518) Google Scholar, 30Johnson R.S. Davis M.T. Taylor J.A. Patterson S.D. Informatics for protein identification by mass spectrometry.Methods. 2005; 35: 223-236Crossref PubMed Scopus (97) Google Scholar, 31Kiehntopf M. Siegmund R. Deufel T. Use of SELDI-TOF mass spectrometry for identification of new biomarkers: potential and limitations.Clin. Chem. Lab. Med. 2007; 45: 1435-1449Crossref PubMed Scopus (79) Google Scholar). The first separates proteins based on isoelectric point (pI) and molecular size, using two-dimensional (2D) gel electrophoresis (32O'Farrell P.H. High resolution two-dimensional electrophoresis of proteins.J. Biol. Chem. 1975; 250: 4007-4021Abstract Full Text PDF PubMed Google Scholar). Protein spots are visualized by staining and extracted from the gel. Following proteolytic digestion, peptides are analyzed with MS and/or MS/MS. This approach can be useful for quantifying proteomes of limited complexity that contain proteins that are relatively abundant. 2D gel electrophoresis is also a powerful strategy for identifying different isoforms or posttranslational modifications of the same protein. However, this analytical strategy also suffers from many limitations; for example: i) it can be difficult to reproducibly analyze multiple samples; ii) extraction and analysis of multiple protein spots by MS is laborious; iii) individual gel spots generally contain more than one protein, which complicates protein quantification; and iv) large, hydrophobic proteins, such as apoB, are unable to enter gels (33Karlsson H. Leanderson P. Tagesson C. Lindahl M. Lipoproteomics II: mapping of proteins in high-density lipoprotein using two-dimensional gel electrophoresis and mass spectrometry.Proteomics. 2005; 5: 1431-1445Crossref PubMed Scopus (150) Google Scholar, 34Karlsson H. Leanderson P. Tagesson C. Lindahl M. Lipoproteomics I: mapping of proteins in low-density lipoprotein using two-dimensional gel electrophoresis and mass spectrometry.Proteomics. 2005; 5: 551-565Crossref PubMed Scopus (117) Google Scholar, 35Karlsson H. Lindqvist H. Tagesson C. Lindahl M. Characterization of apolipoprotein M isoforms in low-density lipoprotein.J. Proteome Res. 2006; 5: 2685-2690Crossref PubMed Scopus (20) Google Scholar, 36Kunitake S.T. Carilli C.T. Lau K. Protter A.A. Naya-Vigne J. Kane J.P. Identification of proteins associated with apolipoprotein A-I-containing lipoproteins purified by selected-affinity immunosorption.Biochemistry. 1994; 33: 1988-1993Crossref PubMed Scopus (51) Google Scholar, 37Mancone C. Amicone L. Fimia G.M. Bravo E. Piacentini M. Tripodi M. Alonzi T. Proteomic analysis of human very low-density lipoprotein by two-dimensional gel electrophoresis and MALDI-TOF/TOF.Proteomics. 2007; 7: 143-154Crossref PubMed Scopus (43) Google Scholar, 38Rezaee F. Casetta B. Levels J.H.M. Speijer D. 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MALDI- and ESI-MS of the HDL apolipoproteins; new isoforms of apoA-I, II.Int. J. Mass Spectrom. 2002; 219: 671-680Crossref Scopus (27) Google Scholar, 42Davidsson P. Hulthe J. Fagerberg B. Olsson B.M. Hallberg C. Dahllof B. Camejo G. A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes.J. Lipid Res. 2005; 46: 1999-2006Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 43Farwig Z.N. Campbell A.V. Macfarlane R.D. Analysis of high-density lipoprotein apolipoproteins recovered from specific immobilized pH gradient gel pI domains by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.Anal. Chem. 2003; 75: 3823-3830Crossref PubMed Scopus (14) Google Scholar, 44Heller M. Stalder D. Schlappritzi E. Hayn G. Matter U. Haeberli A. Mass spectrometry-based analytical tools for the molecular protein characterization of human plasma lipoproteins.Proteomics. 2005; 5: 2619-2630Crossref PubMed Scopus (67) Google Scholar, 45Levels J.H.M. Bleijlevens B. Rezaee F. Aerts J. Meijers J.C.M. SELDI-TOF mass spectrometry of high-density lipoprotein.Proteome Sci. 2007; 5: 15-22Crossref PubMed Scopus (17) Google Scholar, 46Watanabe J. Chou K.J. Liao J.C. Miao Y. Meng H.H. Ge H. Grijalva V. Hama S. Kozak K. Buga G. et al.Differential association of hemoglobin with proinflammatory high density lipoproteins in atherogenic/hyperlipidemic mice. A novel biomarker of atherosclerosis.J. Biol. Chem. 2007; 282: 23698-23707Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Because the mass of an intact protein offers limited diagnostic information, this method is generally limited to identifying known proteins. It also is best applied to the detection of relatively small proteins (typically less than 35 kDa). Protein quantification by MALDI-TOF-MS can also be problematic, and this approach also suffers from a limited dynamic range. Thus, MADLI-TOF-MS is typically limited to detecting relatively abundant proteins that are already known to exist in lipoproteins (such as apoC, apoA, and apoE and their isoforms). The third approach, termed shotgun proteomics (47Washburn M.P. Wolters D. Yates 3rd., J.R. Large-scale analysis of the yeast proteome by multidimensional protein identification technology.Nat. Biotechnol. 2001; 19: 242-247Crossref PubMed Scopus (4029) Google Scholar), uses liquid chromatography (LC) in concert with electrospray ionization and tandem MS analysis (LC-ESI-MS/MS) to identify peptides. The peptide digest is separated by LC, introduced into the gas phase by ESI, and analyzed by tandem MS (15Vaisar T. Pennathur S. Green P.S. Gharib S.A. Hoofnagle A.N. Cheung M.C. Byun J. Vuletic S. Kassim S. Singh P. et al.Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.J. Clin. Invest. 2007; 117: 746-756Crossref PubMed Scopus (772) Google Scholar, 48Green P.S. Vaisar T. Pennathur S. Kulstad J.J. Moore A.B. Marcovina S. Brunzell J. Knopp R.H. Zhao X.Q. Heinecke J.W. Combined statin and niacin therapy remodels the high-density lipoprotein proteome.Circulation. 2008; 118: 1259-1267Crossref PubMed Scopus (114) Google Scholar, 49Heller M. Schlappritzi E. Stalder D. Nuoffer J.M. Haeberli A. Compositional protein analysis of high density lipoproteins in hypercholesterolemia by shotgun LC-MS/MS and probabilistic peptide scoring.Mol. Cell. Proteomics. 2007; 6: 1059-1072Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). To identify the proteins in the original mixture, the MS/MS spectrum collected for each peptide is searched against a database of all the theoretical spectra for a digest of the relevant genome. This method is powerful and can detect more than a thousand proteins and their posttranslational modifications in a single sample. It also is readily applied to the analysis of large numbers of samples, which is critical for clinical and translational studies. Data-base searching can be time-consuming and the analyses expensive, however (47Washburn M.P. Wolters D. Yates 3rd., J.R. Large-scale analysis of the yeast proteome by multidimensional protein identification technology.Nat. Biotechnol. 2001; 19: 242-247Crossref PubMed Scopus (4029) Google Scholar), and protein quantification by this method is generally semi-quantitative. Identification of proteins by MS/MS generally involves the analysis of peptide digests (29Gorg A. Weiss W. Dunn M.J. Current two-dimensional electrophoresis technology for proteomics.Proteomics. 2004; 4: 3665-3685Crossref PubMed Scopus (1518) Google Scholar, 30Johnson R.S. Davis M.T. Taylor J.A. Patterson S.D. Informatics for protein identification by mass spectrometry.Methods. 2005; 35: 223-236Crossref PubMed Scopus (97) Google Scholar, 31Kiehntopf M. Siegmund R. Deufel T. Use of SELDI-TOF mass spectrometry for identification of new biomarkers: potential and limitations.Clin. Chem. Lab. Med. 2007; 45: 1435-1449Crossref PubMed Scopus (79) Google Scholar). Proteins that associate with lipids contain sizable hydrophobic portions that are stabilized by strong secondary structural features and these regions can resist complete proteolytic digestion (50MacCoss M.J. Yates 3rd., J.R. Proteomics: analytical tools and techniques.Curr. Opin. Clin. Nutr. Metab. Care. 2001; 4: 369-375Crossref PubMed Scopus (33) Google Scholar, 51Vaisar T. Proteomic analysis of lipid-protein complexes.J. Lipid Res. 2009; 50: 781-786Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). In addition, the lipids in lipoproteins make protein digestion and mass spectrometric analysis challenging. However, recent technical advances have addressed many of these issues (reviewed in Ref. 51Vaisar T. Proteomic analysis of lipid-protein complexes.J. Lipid Res. 2009; 50: 781-786Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). It is important to note that the method used to isolate lipoproteins significantly affects the protein content of the resulting particles (52Scanu A.M. Edelstein C. HDL: bridging past and present with a look at the future.FASEB J. 2008; 22: 4044-4054Crossref PubMed Scopus (104) Google Scholar). Most proteomic studies have relied on ultracentrifugation, which is convenient because particle classes are defined by density and ultracentrifugation is widely used for clinical studies. However, the typical isolation involves high concentrations of KBr, a potent chaotropic agent, which can dissociate proteins from lipoproteins (53Curry M.D. Alaupovic P. Suenram C. 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• W2045790812 created "2016-06-24" @default.
• W2045790812 creator A5031218554 @default.
• W2045790812 creator A5035595391 @default.
• W2045790812 date "2009-10-01" @default.
• W2045790812 modified "2023-10-18" @default.
• W2045790812 title "Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structure, and function of lipoproteins" @default.
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• W2045790812 doi "https://doi.org/10.1194/jlr.r900015-jlr200" @default.
• W2045790812 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2739765" @default.
• W2045790812 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19738003" @default.
• W2045790812 hasPublicationYear "2009" @default.

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