Unraveling the complexities of the HDL lipidome
2013; Elsevier BV; Volume: 54; Issue: 11 Linguagem: Inglês
10.1194/jlr.r036095
ISSN1539-7262
AutoresAnatol Kontush, Marie Lhomme, M. John Chapman,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoPlasma high density lipoproteins (HDL) are small, dense, protein-rich particles compared with other lipoprotein classes; roughly half of total HDL mass is accounted for by lipid components. Phospholipids predominate in the HDL lipidome, accounting for 40–60% of total lipid, with lesser proportions of cholesteryl esters (30–40%), triglycerides (5–12%), and free cholesterol (5–10%). Lipidomic approaches have provided initial insights into the HDL lipidome with identification of over 200 individual molecular lipids species in normolipidemic HDL. Plasma HDL particles, however, reveal high levels of structural, compositional, and functional heterogeneity. Establishing direct relationships between HDL structure, composition, and atheroprotective functions bears the potential to identify clinically relevant HDL subpopulations. Furthermore, development of HDL-based therapies designed to target beneficial subspecies within the circulating HDL pool can be facilitated using this approach. HDL lipidomics can equally contribute to the identification of biomarkers of both normal and deficient HDL functionality, which may prove useful as biomarkers of cardiovascular risk. However, numerous technical issues remain to be addressed in order to make such developments possible. With all technical questions resolved, quantitative analysis of the molecular components of the HDL lipidome will contribute to expand our knowledge of cardiovascular and metabolic diseases. Plasma high density lipoproteins (HDL) are small, dense, protein-rich particles compared with other lipoprotein classes; roughly half of total HDL mass is accounted for by lipid components. Phospholipids predominate in the HDL lipidome, accounting for 40–60% of total lipid, with lesser proportions of cholesteryl esters (30–40%), triglycerides (5–12%), and free cholesterol (5–10%). Lipidomic approaches have provided initial insights into the HDL lipidome with identification of over 200 individual molecular lipids species in normolipidemic HDL. Plasma HDL particles, however, reveal high levels of structural, compositional, and functional heterogeneity. Establishing direct relationships between HDL structure, composition, and atheroprotective functions bears the potential to identify clinically relevant HDL subpopulations. Furthermore, development of HDL-based therapies designed to target beneficial subspecies within the circulating HDL pool can be facilitated using this approach. HDL lipidomics can equally contribute to the identification of biomarkers of both normal and deficient HDL functionality, which may prove useful as biomarkers of cardiovascular risk. However, numerous technical issues remain to be addressed in order to make such developments possible. With all technical questions resolved, quantitative analysis of the molecular components of the HDL lipidome will contribute to expand our knowledge of cardiovascular and metabolic diseases. High density lipoproteins (HDL) are small, dense, protein-rich particles compared with other plasma lipoprotein classes. Despite the elevated abundance of multiple structural and functional proteins in HDL particles (see other reviews in this Thematic Series), roughly half of total HDL mass is accounted for by lipid components. For many years, HDL lipids were predominantly characterized in terms of the content of their major classes, notably phospholipids, unesterified (free) sterols (predominantly cholesterol), cholesteryl esters, and triglycerides. Cholesterol is the most characteristic component of the HDL lipidome as, in the form of HDL-cholesterol, it represents a major independent negative risk factor for cardiovascular disease (see other reviews in this Thematic Series). It is not cholesterol, however, but phospholipids that quantitatively predominate in the HDL lipidome, accounting, together with sphingomyelin (SM), for 40–60 wt% of total lipid, with lesser proportions of cholesteryl esters (30–40%), triglycerides (5–12%), and free cholesterol (5–10%). Structurally, individual HDL lipid classes fulfill distinct functions; phospholipids constitute the surface lipid monolayer of HDL, whereas cholesteryl esters and triglycerides form the hydrophobic lipid core. Unesterified sterols are predominantly located to the surface monolayer, partially penetrating the core. Recent technological advances in mass spectrometry (MS) have enabled application of this powerful technique to provide a detailed identification and quantification of individual molecular species of lipids in the framework of the field known as lipidomics. Application of this approach to plasma lipoproteins has revealed complex profiles consisting of hundreds of molecular lipid species that have been quantified in major lipoprotein classes, including HDL (reviewed in Refs. 1Kontush A. Chapman M.J. Lipidomics as a tool for the study of lipoprotein metabolism.Curr. Atheroscler. Rep. 2010; 12: 194-201Crossref PubMed Scopus (41) Google Scholar, 2Scherer M. Bottcher A. Liebisch G. Lipid profiling of lipoproteins by electrospray ionization tandem mass spectrometry.Biochim. Biophys. Acta. 2011; 1811: 918-924Crossref PubMed Scopus (23) Google Scholar, 3Kontush A. Chapman M.J. High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. Wiley & Sons, New York2012Google Scholar). Our current knowledge of the HDL lipidome involves more than 200 individual molecular lipids species identified by recent lipidomic analyses (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 5Yetukuri L. Soderlund S. Koivuniemi A. Seppanen-Laakso T. Niemela P.S. Hyvonen M. Taskinen M-R. Vattulainen I. Jauhiainen M. Oresic M. Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol.J. Lipid Res. 2010; 51: 2341-2351Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar); this number is primarily limited by the sensitivity of the available technologies and will inevitably expand in the near future (6Quehenberger O. Armando A.M. Brown A.H. Milne S.B. Myers D.S. Merrill A.H. Bandyopadhyay S. Jones K.N. Kelly S. Shaner R.L. et al.Lipidomics reveals a remarkable diversity of lipids in human plasma.J. Lipid Res. 2010; 51: 3299-3305Abstract Full Text Full Text PDF PubMed Scopus (746) Google Scholar). In this article, we will review data on the composition and functional significance of the HDL lipidome in health and disease, focusing on both traditional measurements of its content of major lipid classes and on modern lipidomic approaches to quantify individual lipid species. Phospholipids represent the major component of the HDL lipidome, accounting for approximately half of all lipids on a weight basis (Table 1). Phosphatidylcholine (PC) predominates as the principal molecular class of phospholipids in HDL. In addition, HDL contains smaller but still significant amounts (≥1 wt% of total HDL lipids) of lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and plasmalogens (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Kontush A. Therond P. Zerrad A. Couturier M. Negre-Salvayre A. de Souza J.A. Chantepie S. Chapman M.J. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar, 8Scherer M. Bottcher A. Schmitz G. Liebisch G. Sphingolipid profiling of human plasma and FPLC-separated lipoprotein fractions by hydrophilic interaction chromatography tandem mass spectrometry.Biochim. Biophys. Acta. 2011; 1811: 68-75Crossref PubMed Scopus (60) Google Scholar) (Table 1). Minor HDL phospholipids (<1 wt% of total HDL lipids) are represented by phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidic acid (PA) and cardiolipin (5Yetukuri L. Soderlund S. Koivuniemi A. Seppanen-Laakso T. Niemela P.S. Hyvonen M. Taskinen M-R. Vattulainen I. Jauhiainen M. Oresic M. Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol.J. Lipid Res. 2010; 51: 2341-2351Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 9Lee J.Y. Min H.K. Choi D. Moon M.H. Profiling of phospholipids in lipoproteins by multiplexed hollow fiber flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry.J. Chromatogr. A. 2010; 1217: 1660-1666Crossref PubMed Scopus (0) Google Scholar, 10Deguchi H. Fernandez J.A. Hackeng T.M. Banka C.L. Griffin J.H. Cardiolipin is a normal component of human plasma lipoproteins.Proc. Natl. Acad. Sci. USA. 2000; 97: 1743-1748Crossref PubMed Scopus (0) Google Scholar).TABLE 1Major components of the HDL lipidomeLipid ClassHDL ContentaDepending on the specific HDL subpopulation, lipids constitute from 30% to 70% of total HDL mass (145). (wt% of total HDL lipid)Major SubspeciesRefs.Phospholipids35–50Phosphatidylcholine(4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Kontush A. Therond P. Zerrad A. Couturier M. Negre-Salvayre A. de Souza J.A. Chantepie S. Chapman M.J. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar, 38Skipski V.P. Barclay M. Barclay R.K. Fetzer V.A. Good J.J. Archibald F.M. Lipid composition of human serum lipoproteins.Biochem. J. 1967; 104: 340-352Crossref PubMed Google Scholar)Phosphatidylcholine33–4516:0/18:2, 18:0/18:2, 16:0/20:4, 16:0/18:1(4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Kontush A. Therond P. Zerrad A. Couturier M. Negre-Salvayre A. de Souza J.A. Chantepie S. Chapman M.J. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar, 38Skipski V.P. Barclay M. Barclay R.K. Fetzer V.A. Good J.J. Archibald F.M. Lipid composition of human serum lipoproteins.Biochem. J. 1967; 104: 340-352Crossref PubMed Google Scholar)Lysophosphatidylcholine0.5–516:0, 18:0, 18:1, 18:2(4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. 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A. 2010; 1217: 1660-1666Crossref PubMed Scopus (0) Google Scholar, 13Pruzanski W. Stefanski E. de Beer F.C. de Beer M.C. Ravandi A. Kuksis A. Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.J. Lipid Res. 2000; 41: 1035-1047Abstract Full Text Full Text PDF PubMed Google Scholar, 38Skipski V.P. Barclay M. Barclay R.K. Fetzer V.A. Good J.J. Archibald F.M. Lipid composition of human serum lipoproteins.Biochem. J. 1967; 104: 340-352Crossref PubMed Google Scholar)Plasmalogens0.5–1.518:0/20:4, 16:0/20:4, 18:1/20:4, 18:0/18:2, 16:0/22:6(4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar)Phosphatidylserine0.02–0.0416:0/18:0(5Yetukuri L. Soderlund S. Koivuniemi A. Seppanen-Laakso T. Niemela P.S. Hyvonen M. Taskinen M-R. Vattulainen I. Jauhiainen M. Oresic M. Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol.J. Lipid Res. 2010; 51: 2341-2351Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 10Deguchi H. Fernandez J.A. Hackeng T.M. Banka C.L. Griffin J.H. Cardiolipin is a normal component of human plasma lipoproteins.Proc. Natl. Acad. Sci. USA. 2000; 97: 1743-1748Crossref PubMed Scopus (0) Google Scholar, 38Skipski V.P. Barclay M. Barclay R.K. Fetzer V.A. Good J.J. Archibald F.M. Lipid composition of human serum lipoproteins.Biochem. J. 1967; 104: 340-352Crossref PubMed Google Scholar)PhosphatidylglycerolND18:1/20:2(9Lee J.Y. Min H.K. Choi D. Moon M.H. Profiling of phospholipids in lipoproteins by multiplexed hollow fiber flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry.J. Chromatogr. 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Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar)Sphingosylphosphorylcholine0.0005(30Nofer J-R. Assmann G. Atheroprotective effects of high-density lipoprotein-associated lysosphingolipids.Trends Cardiovasc. Med. 2005; 15: 265-271Crossref PubMed Scopus (83) Google Scholar)Steroids5–10Cholesterol(36Burkard I. von Eckardstein A. Waeber G. Vollenweider P. Rentsch K.M. Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers.Atherosclerosis. 2007; 194: 71-78Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 37Tikkanen M.J. Vihma V. Jauhiainen M. Hockerstedt A. Helisten H. Kaamanen M. Lipoprotein-associated estrogens.Cardiovasc. 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Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar, 38Skipski V.P. Barclay M. Barclay R.K. Fetzer V.A. Good J.J. Archibald F.M. Lipid composition of human serum lipoproteins.Biochem. J. 1967; 104: 340-352Crossref PubMed Google Scholar)Modified from Ref. 3Kontush A. Chapman M.J. High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. Wiley & Sons, New York2012Google Scholar. ND, not determined.a Depending on the specific HDL subpopulation, lipids constitute from 30% to 70% of total HDL mass (145Kontush A. Chantepie S. Chapman M.J. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1881-1888Crossref PubMed Scopus (310) Google Scholar). Open table in a new tab Modified from Ref. 3Kontush A. Chapman M.J. High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. Wiley & Sons, New York2012Google Scholar. ND, not determined. Phospholipids are unequally distributed in the circulation across lipoproteins. As a result of enrichment in phospholipids, HDL represents a major carrier of PC, LPC, PE, and PE-derived plasmalogens, containing over 50% of each of these lipid classes present in human serum (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). PC is the key structural phospholipid of cell membranes and lipoproteins, and represents the principal plasma phospholipid that accounts for 33–45 wt% of total lipid in HDL (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar) (Table 1). The 16:0/18:2, 18:0/18:2, 16:0/20:4, and 16:0/18:1 species constitute major molecular species of HDL PC (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 9Lee J.Y. Min H.K. Choi D. Moon M.H. Profiling of phospholipids in lipoproteins by multiplexed hollow fiber flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry.J. Chromatogr. A. 2010; 1217: 1660-1666Crossref PubMed Scopus (0) Google Scholar, 11Stahlman M. Pham H.T. Adiels M. Mitchell T.W. Blanksby S.J. Fagerberg B. Ekroos K. Boren J. Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes.Diabetologia. 2012; 55: 1156-1166Crossref PubMed Scopus (0) Google Scholar, 12Hidaka H. Yamauchi K. Ohta H. Akamatsu T. Honda T. Katsuyama T. Specific, rapid, and sensitive enzymatic measurement of sphingomyelin, phosphatidylcholine and lysophosphatidylcholine in serum and lipid extracts.Clin. Biochem. 2008; 41: 1211-1217Crossref PubMed Scopus (20) Google Scholar, 13Pruzanski W. Stefanski E. de Beer F.C. de Beer M.C. Ravandi A. Kuksis A. Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins.J. Lipid Res. 2000; 41: 1035-1047Abstract Full Text Full Text PDF PubMed Google Scholar). Relative to other lipoproteins, HDL is enriched in PC containing polyunsaturated fatty acid (PUFA) moieties (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). HDL PC can be of both hepatic (via formation of nascent lipoprotein particles) and extrahepatic [via the actions of phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP)] origin. LPC, which is the product of PC hydrolysis in the lecithin:cholesterol acyltransferase (LCAT) reaction, constitutes a quantitatively important subclass of phospholipids in HDL [up to 15 wt% in HDL isolated by fast performance liquid chromatography (FPLC)] compared with apolipoprotein (apo)B-containing lipoproteins (2–3 wt%) (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 11Stahlman M. Pham H.T. Adiels M. Mitchell T.W. Blanksby S.J. Fagerberg B. Ekroos K. Boren J. Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes.Diabetologia. 2012; 55: 1156-1166Crossref PubMed Scopus (0) Google Scholar) (Table 1). The preferential association of LPC with HDL is consistent with the predominant occurrence of the LCAT reaction in this lipoprotein (7Kontush A. Therond P. Zerrad A. Couturier M. Negre-Salvayre A. de Souza J.A. Chantepie S. Chapman M.J. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar). As considerable amounts of serum LPC are also associated with albumin (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar), HDL contamination by the latter as typically occurs upon FPLC isolation can overestimate the amount of this lipid in the HDL fraction isolated by this approach. Major molecular species of HDL LPC carry palmitic and stearic acid moieties (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 11Stahlman M. Pham H.T. Adiels M. Mitchell T.W. Blanksby S.J. Fagerberg B. Ekroos K. Boren J. Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes.Diabetologia. 2012; 55: 1156-1166Crossref PubMed Scopus (0) Google Scholar), reflecting LCAT preference for 16 and 18 carbon atom PCs (14Subbaiah P.V. Liu M. Disparate effects of oxidation on plasma acyltransferase activities: inhibition of cholesterol esterification but stimulation of transesterification of oxidized phospholipids.Biochim. Biophys. Acta. 1996; 1301: 115-126Crossref PubMed Scopus (24) Google Scholar). Interestingly, the 16:0 LPC is enriched in HDL, whereas the 18:0 species is predominantly associated with very low density lipoprotein (VLDL) and low density lipoprotein (LDL), potentially reflecting distinct metabolic pathways for individual LPC molecules. PE is another important structural phospholipid that accounts for approximately 1 wt% of HDL lipid (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar) (Table 1). Principal plasma PEs are represented by the 36:2 and 38:4 species, which are evenly distributed across VLDL, LDL, and HDL (7Kontush A. Therond P. Zerrad A. Couturier M. Negre-Salvayre A. de Souza J.A. Chantepie S. Chapman M.J. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1843-1849Crossref PubMed Scopus (160) Google Scholar). PE plasmalogens are minor plasma phospholipids with antioxidative properties (15Maeba R. Ueta N. Ethanolamine plasmalogen and cholesterol reduce the total membrane oxidizability measured by the oxygen uptake method.Biochem. Biophys. Res. Commun. 2003; 302: 265-270Crossref PubMed Scopus (0) Google Scholar, 16Maeba R. Ueta N. Ethanolamine plasmalogens prevent the oxidation of cholesterol by reducing the oxidizability of cholesterol in phospholipid bilayers.J. Lipid Res. 2003; 44: 164-171Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 17Maeba R. Sawada Y. Shimasaki H. Takahashi I. Ueta N. Ethanolamine plasmalogens protect cholesterol-rich liposomal membranes from oxidation caused by free radicals.Chem. Phys. Lipids. 2002; 120: 145-151Crossref PubMed Scopus (16) Google Scholar) present in HDL at approximately 1 wt % of lipid (4Wiesner P. Leidl K. Boettcher A. Schmitz G. Liebisch G. Lipid profiling of FPLC-separated lipoprotein fractions by electrospray ionization tandem mass spectrometry.J. Lipid Res. 2009; 50: 574-585Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar) (Table 1). 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