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The Underlying Chemistry of Electronegative LDL’s Atherogenicity

  • Genetics (AJ Marian, Section Editor)
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Abstract

Electronegative low-density lipoprotein (LDL) found in human plasma is highly atherogenic, and its level is elevated in individuals with increased cardiovascular risk. In this review, we summarize the available data regarding the elevation of the levels of electronegative LDL in the plasma of patients with various diseases. In addition, we discuss the harmful effects and underlying mechanisms of electronegative LDL in various cell types. We also highlight the known biochemical properties of electronegative LDL that may contribute to its atherogenic functions, including its lipid and protein composition, enzymatic activities, and structural features. Given the increasing recognition of electronegative LDL as a potential biomarker and therapeutic target for the prevention of cardiovascular disease, key future goals include the development of a standard method for the detection of electronegative LDL that can be used in a large-scale population survey and the identification and testing of strategies for eliminating electronegative LDL from the blood.

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References

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  1. Goff Jr DC, Lloyd-Jones DM, Bennett G, et al. ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013. doi:10.1016/j.jacc.2013.11.00.

    PubMed  Google Scholar 

  2. Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013. doi:10.1016/j.jacc.2013.11.002.

    PubMed Central  Google Scholar 

  3. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1, CD004816.

    PubMed  Google Scholar 

  4. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–61.

    Article  CAS  PubMed  Google Scholar 

  5. Gissi HFI, Tavazzi L, Maggioni AP, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–9.

    Article  Google Scholar 

  6. Schwandt P, Liepold E, Bertsch T, Haas GM. Lifestyle, cardiovascular drugs and risk factors in younger and elder adults: the PEP Family Heart Study. Int J Prev Med. 2010;1:56–61.

    PubMed Central  PubMed  Google Scholar 

  7. Yasue H, Hirai N, Mizuno Y, et al. Low-grade inflammation, thrombogenicity, and atherogenic lipid profile in cigarette smokers. Circ J. 2006;70:8–13.

    Article  PubMed  Google Scholar 

  8. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.

    Article  CAS  PubMed  Google Scholar 

  9. Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol. 2012;8:214–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Ruiz-Limon P, Barbarroja N, Perez-Sanchez C, et al. Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204351.

    Google Scholar 

  11. Marian AJ. The enigma of genetics etiology of atherosclerosis in the post-GWAS era. Curr Atheroscler Rep. 2012;14:295–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Chung CP, Solus JF, Oeser A, et al. Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus. Lupus. 2014. doi:10.1177/0961203314530019.

    Google Scholar 

  13. Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation. 2004;109:III2–7.

    Article  PubMed  Google Scholar 

  14. Koba S, Hirano T, Ito Y, et al. Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases. Atherosclerosis. 2006;189:206–14.

    Article  CAS  PubMed  Google Scholar 

  15. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  CAS  PubMed  Google Scholar 

  16. Witztum JL, Steinberg D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med. 2001;11:93–102.

    Article  CAS  PubMed  Google Scholar 

  17. Itabe H, Yamamoto H, Imanaka T, et al. Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody. J Lipid Res. 1996;37:45–53.

    CAS  PubMed  Google Scholar 

  18. Palinski W, Horkko S, Miller E, et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996;98:800–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Mello AP, da Silva IT, Abdalla DS, Damasceno NR. Electronegative low-density lipoprotein: origin and impact on health and disease. Atherosclerosis. 2011;215:257–65.

    Article  CAS  PubMed  Google Scholar 

  20. Sanchez-Quesada JL, Villegas S, Ordonez-Llanos J. Electronegative low-density lipoprotein. A link between apolipoprotein B misfolding, lipoprotein aggregation and proteoglycan binding. Curr Opin Lipidol. 2012;23:479–86.

    Article  CAS  PubMed  Google Scholar 

  21. Hoff HF, Gaubatz JW. Isolation, purification, and characterization of a lipoprotein containing apo B from the human aorta. Atherosclerosis. 1982;42:273–97.

    Article  CAS  PubMed  Google Scholar 

  22. Hoff HF, Karagas M, Heideman CL, et al. Correlation in the human aorta of apo B fractions with tissue cholesterol and collagen content. Atherosclerosis. 1979;32:259–68.

    Article  CAS  PubMed  Google Scholar 

  23. Avogaro P, Bon GB, Cazzolato G. Presence of a modified low density lipoprotein in humans. Arteriosclerosis. 1988;8:79–87.

    Article  CAS  PubMed  Google Scholar 

  24. Chen CH, Jiang T, Yang JH, et al. Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation. 2003;107:2102–8.

    Article  PubMed  Google Scholar 

  25. Yang CY, Raya JL, Chen HH, et al. Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. Arterioscler Thromb Vasc Biol. 2003;23:1083–90.

    Article  CAS  PubMed  Google Scholar 

  26. Lu J, Yang JH, Burns AR, et al. Mediation of electronegative low-density lipoprotein signaling by LOX-1: a possible mechanism of endothelial apoptosis. Circ Res. 2009;104:619–27.

    Article  CAS  PubMed  Google Scholar 

  27. Lee AS, Wang GJ, Chan HC, et al. Electronegative low-density lipoprotein induces cardiomyocyte apoptosis indirectly through endothelial cell-released chemokines. Apoptosis. 2012;17:1009–18. L5 indirectly induced cardiomyocyte apoptosis by enhancing secretion of ELR-positive CXC chemokines from ECs, which in turn activate CXCR2/phosphoinositide 3-kinase/NF-κB signaling to increase the release of tumor necrosis factor α and IL-1β.

    Article  CAS  PubMed  Google Scholar 

  28. Chu CS, Wang YC, Lu LS, et al. Electronegative low-density lipoprotein increases C-reactive protein expression in vascular endothelial cells through the LOX-1 receptor. PLoS One. 2013;8, e70533. L5 induces C-reactive protein expression and reactive oxygen species production in vitro, and its levels are reduced in the plasma of hypercholesterolemic patients treated with atorvastatin.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Gaubatz JW, Gillard BK, Massey JB, et al. Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A2. J Lipid Res. 2007;48:348–57.

    Article  CAS  PubMed  Google Scholar 

  30. Tang D, Lu J, Walterscheid JP, et al. Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. J Lipid Res. 2008;49:33–47.

    Article  CAS  PubMed  Google Scholar 

  31. Urata J, Ikeda S, Koga S, et al. Negatively charged low-density lipoprotein is associated with atherogenic risk in hypertensive patients. Heart Vessels. 2012;27:235–42.

    Article  PubMed  Google Scholar 

  32. Chan HC, Ke LY, Chu CS, et al. Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation. Blood. 2013;122:3632–41. L5 concentration is increased in the plasma of patients with STEMI and enhances ADP-stimulated platelet aggregation and platelet–EC adhesion in vitro, suggesting a role for L5 in thrombogenesis.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Oliveira JA, Sevanian A, Rodrigues RJ, et al. Minimally modified electronegative LDL and its autoantibodies in acute and chronic coronary syndromes. Clin Biochem. 2006;39:708–14.

    Article  CAS  PubMed  Google Scholar 

  34. Lobo J, Santos F, Grosso D, et al. Electronegative LDL and lipid abnormalities in patients undergoing hemodialysis and peritoneal dialysis. Nephron Clin Pract. 2008;108:c298–304.

    Article  CAS  PubMed  Google Scholar 

  35. Sawamura T, Kakino A, Fujita Y. LOX-1: a multiligand receptor at the crossroads of response to danger signals. Curr Opin Lipidol. 2012;23:439–45. Among various LOX-1 ligands, L5 and its interaction with LOX-1 are discussed in the context of the pathophysiological significance of LOX-1.

    Article  CAS  PubMed  Google Scholar 

  36. Lu J, Jiang W, Yang JH, et al. Electronegative LDL impairs vascular endothelial cell integrity in diabetes by disrupting fibroblast growth factor 2 (FGF2) autoregulation. Diabetes. 2008;57:158–66.

    Article  CAS  PubMed  Google Scholar 

  37. Chen HH, Hosken BD, Huang M, et al. Electronegative LDLs from familial hypercholesterolemic patients are physicochemically heterogeneous but uniformly proapoptotic. J Lipid Res. 2007;48:177–84.

    Article  CAS  PubMed  Google Scholar 

  38. Sanchez-Quesada JL, Camacho M, Anton R, et al. Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells. Atherosclerosis. 2003;166:261–70.

    Article  CAS  PubMed  Google Scholar 

  39. Tai MH, Kuo SM, Liang HT, et al. Modulation of angiogenic processes in cultured endothelial cells by low density lipoproteins subfractions from patients with familial hypercholesterolemia. Atherosclerosis. 2006;186:448–57.

    Article  CAS  PubMed  Google Scholar 

  40. von Eckardstein A, Rohrer L. Transendothelial lipoprotein transport and regulation of endothelial permeability and integrity by lipoproteins. Curr Opin Lipidol. 2009;20:197–205.

    Article  Google Scholar 

  41. Estruch M, Sanchez-Quesada JL, Beloki L, et al. The induction of cytokine release in monocytes by electronegative low-density lipoprotein (LDL) is related to its higher ceramide content than native LDL. Int J Mol Sci. 2013;14:2601–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Abe Y, Fornage M, Yang CY, et al. L5, the most electronegative subfraction of plasma LDL, induces endothelial vascular cell adhesion molecule 1 and CXC chemokines, which mediate mononuclear leukocyte adhesion. Atherosclerosis. 2007;192:56–66.

    Article  CAS  PubMed  Google Scholar 

  43. De Castellarnau C, Sanchez-Quesada JL, Benitez S, et al. Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells. Arterioscler Thromb Vasc Biol. 2000;20:2281–7.

    Article  PubMed  Google Scholar 

  44. Nichols TC. Bad cholesterol breaking really bad. Blood. 2013;122:3551–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Benitez S, Perez A, Sanchez-Quesada JL, et al. Electronegative low-density lipoprotein subfraction from type 2 diabetic subjects is proatherogenic and unrelated to glycemic control. Diabetes Metab Res Rev. 2007;23:26–34.

    Article  CAS  PubMed  Google Scholar 

  46. Ke LY, Engler DA, Lu J, et al. Chemical composition-oriented receptor selectivity of L5, a naturally occurring atherogenic low-density lipoprotein. Pure Appl Chem. 2011;83. A proteomic study of L5 showing that additional apolipoproteins in L5 contribute to its electronegativity and receptor selectivity.

  47. Chappey B, Myara I, Benoit MO, et al. Characteristics of ten charge-differing subfractions isolated from human native low-density lipoproteins (LDL). No evidence of peroxidative modifications. Biochim Biophys Acta. 1995;1259:261–70.

    Article  PubMed  Google Scholar 

  48. Moro E, Alessandrini P, Zambon C, et al. Is glycation of low density lipoproteins in patients with type 2 diabetes mellitus a LDL pre-oxidative condition? Diabet Med. 1999;16:663–9.

    Article  CAS  PubMed  Google Scholar 

  49. Geromanos SJ, Vissers JP, Silva JC, et al. The detection, correlation, and comparison of peptide precursor and product ions from data independent LC-MS with data dependant LC-MS/MS. Proteomics. 2009;9:1683–95.

    Article  CAS  PubMed  Google Scholar 

  50. Li GZ, Vissers JP, Silva JC, et al. Database searching and accounting of multiplexed precursor and product ion spectra from the data independent analysis of simple and complex peptide mixtures. Proteomics. 2009;9:1696–719.

    Article  CAS  PubMed  Google Scholar 

  51. Bancells C, Canals F, Benitez S, et al. Proteomic analysis of electronegative low-density lipoprotein. J Lipid Res. 2010;51:3508–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Scheffer PG, Bakker SJ, Heine RJ, Teerlink T. Measurement of low-density lipoprotein particle size by high-performance gel-filtration chromatography. Clin Chem. 1997;43:1904–12.

    CAS  PubMed  Google Scholar 

  53. Tselepis AD, John Chapman M. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. Atheroscler Suppl. 2002;3:57–68.

    Article  CAS  PubMed  Google Scholar 

  54. Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol. 2005;25:923–31.

    Article  CAS  PubMed  Google Scholar 

  55. Sanchez-Quesada JL, Vinagre I, De Juan-Franco E, et al. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes. Cardiovasc Diabetol. 2013;12:112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Yang CY, Chen HH, Huang MT, et al. Pro-apoptotic low-density lipoprotein subfractions in type II diabetes. Atherosclerosis. 2007;193:283–91.

    Article  CAS  PubMed  Google Scholar 

  57. Benitez S, Villegas V, Bancells C, et al. Impaired binding affinity of electronegative low-density lipoprotein (LDL) to the LDL receptor is related to nonesterified fatty acids and lysophosphatidylcholine content. Biochemistry. 2004;43:15863–72.

    Article  CAS  PubMed  Google Scholar 

  58. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60:2441–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Sanchez-Quesada JL, Vinagre I, de Juan-Franco E, et al. Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution. Am J Cardiol. 2012;110:67–71. Optimal glycemic control in patients with type 2 diabetes promotes atheroprotective changes that include decreased levels of LDL(–).

    Article  CAS  PubMed  Google Scholar 

  60. Benitez S, Camacho M, Arcelus R, et al. Increased lysophosphatidylcholine and non-esterified fatty acid content in LDL induces chemokine release in endothelial cells. Relationship with electronegative LDL. Atherosclerosis. 2004;177:299–305.

    CAS  PubMed  Google Scholar 

  61. Holmes MV, Simon T, Exeter HJ, et al. Secretory phospholipase A2-IIA and cardiovascular disease: a Mendelian randomization study. J Am Coll Cardiol. 2013;62:1966–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Xu H, Valenzuela N, Fai S, et al. Targeted lipidomics - advances in profiling lysophosphocholine and platelet-activating factor second messengers. FEBS J. 2013;280:5652–67.

    Article  CAS  PubMed  Google Scholar 

  63. Benítez S, Sanchez-Quesada JL, Ribas V, et al. Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction. Circulation. 2003;108:92–6.

    Article  PubMed  Google Scholar 

  64. Sanchez-Quesada JL, Benitez S, Perez A, et al. The inflammatory properties of electronegative low-density lipoprotein from type 1 diabetic patients are related to increased platelet-activating factor acetylhydrolase activity. Diabetologia. 2005;48:2162–9.

    Article  CAS  PubMed  Google Scholar 

  65. Ito S, Noguchi E, Shibasaki M, et al. Evidence for an association between plasma platelet-activating factor acetylhydrolase deficiency and increased risk of childhood atopic asthma. J Hum Genet. 2002;47:99–101.

    Article  CAS  PubMed  Google Scholar 

  66. Stafforini DM. Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc Drugs Ther. 2009;23:73–83.

    Article  CAS  PubMed  Google Scholar 

  67. Bancells C, Benitez S, Jauhiainen M, et al. High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level. J Lipid Res. 2009;50:446–55.

    Article  CAS  PubMed  Google Scholar 

  68. Bancells C, Benitez S, Ordonez-Llanos J, et al. Immunochemical analysis of the electronegative LDL subfraction shows that abnormal N-terminal apolipoprotein B conformation is involved in increased binding to proteoglycans. J Biol Chem. 2011;286:1125–33. The amino-terminal region of apo B-100 has an abnormal conformation in LDL(–) that may promote its increased binding to arterial proteoglycans and influence its receptor affinity.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Bancells C, Benitez S, Villegas S, et al. Novel phospholipolytic activities associated with electronegative low-density lipoprotein are involved in increased self-aggregation. Biochemistry. 2008;47:8186–94.

    Article  CAS  PubMed  Google Scholar 

  70. Doehner W, Bunck AC, Rauchhaus M, et al. Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow. Eur Heart J. 2007;28:821–8.

    Article  CAS  PubMed  Google Scholar 

  71. Gorska M, Baranczuk E, Dobrzyn A. Secretory Zn2+-dependent sphingomyelinase activity in the serum of patients with type 2 diabetes is elevated. Horm Metab Res. 2003;35:506–7.

    Article  CAS  PubMed  Google Scholar 

  72. Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab. 2012;15:585–94.

    Article  CAS  PubMed  Google Scholar 

  73. Estruch M, Sanchez-Quesada JL, Ordonez-Llanos J, Benitez S. Ceramide-enriched LDL induces cytokine release through TLR4 and CD14 in monocytes. Similarities with electronegative LDL. Clin Investig Arterioscler. 2014. doi:10.1016/j.arteri.2013.12.003.

    PubMed  Google Scholar 

  74. Yu J, Novgorodov SA, Chudakova D, et al. JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J Biol Chem. 2007;282:25940–9.

    Article  CAS  PubMed  Google Scholar 

  75. Obama T, Kato R, Masuda Y, et al. Analysis of modified apolipoprotein B-100 structures formed in oxidized low-density lipoprotein using LC-MS/MS. Proteomics. 2007;7:2132–41.

    Article  CAS  PubMed  Google Scholar 

  76. Segrest JP, Jones MK, Mishra VK, et al. apoB-100 has a pentapartite structure composed of three amphipathic alpha-helical domains alternating with two amphipathic beta-strand domains. Detection by the computer program LOCATE. Arterioscler Thromb. 1994;14:1674–85.

    Article  CAS  PubMed  Google Scholar 

  77. Walters MJ, Wrenn SP. Effect of sphingomyelinase-mediated generation of ceramide on aggregation of low-density lipoprotein. Langmuir. 2008;24:9642–7.

    Article  CAS  PubMed  Google Scholar 

  78. Oestvang J, Bonnefont-Rousselot D, Ninio E, et al. Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity. J Lipid Res. 2004;45:831–8.

    Article  CAS  PubMed  Google Scholar 

  79. Devlin CM, Leventhal AR, Kuriakose G, et al. Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression. Arterioscler Thromb Vasc Biol. 2008;28:1723–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Hamilton RT, Asatryan L, Nilsen JT, et al. LDL protein nitration: implication for LDL protein unfolding. Arch Biochem Biophys. 2008;479:1–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Parasassi T, Bittolo-Bon G, Brunelli R, et al. Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-). Free Radic Biol Med. 2001;31:82–9.

    Article  CAS  PubMed  Google Scholar 

  82. Holopainen JM, Medina OP, Metso AJ, Kinnunen PK. Sphingomyelinase activity associated with human plasma low density lipoprotein. J Biol Chem. 2000;275:16484–9.

    Article  CAS  PubMed  Google Scholar 

  83. Kinnunen PK, Holopainen JM. Sphingomyelinase activity of LDL: a link between atherosclerosis, ceramide, and apoptosis? Trends Cardiovasc Med. 2002;12:37–42.

    Article  CAS  PubMed  Google Scholar 

  84. Hevonoja T, Pentikainen MO, Hyvonen MT, et al. Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. Biochim Biophys Acta. 2000;1488:189–210.

    Article  CAS  PubMed  Google Scholar 

  85. Yang CY, Kim TW, Weng SA, et al. Isolation and characterization of sulfhydryl and disulfide peptides of human apolipoprotein B-100. Proc Natl Acad Sci U S A. 1990;87:5523–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Zhao Y, McCabe JB, Vance J, Berthiaume LG. Palmitoylation of apolipoprotein B is required for proper intracellular sorting and transport of cholesteroyl esters and triglycerides. Mol Biol Cell. 2000;11:721–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Chen R, Jiang X, Sun D, et al. Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009;8:651–61.

    Article  CAS  PubMed  Google Scholar 

  88. Liu T, Qian WJ, Gritsenko MA, et al. Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005;4:2070–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Yang CY, Gu ZW, Weng SA, et al. Structure of apolipoprotein B-100 of human low density lipoproteins. Arteriosclerosis. 1989;9:96–108.

    Article  CAS  PubMed  Google Scholar 

  90. Sun HY, Chen SF, Lai MD, et al. Comparative proteomic profiling of plasma very-low-density and low-density lipoproteins. Clin Chim Acta. 2010;411:336–44.

    Article  CAS  PubMed  Google Scholar 

  91. Yang CY, Chen SH, Gianturco SH, et al. Sequence, structure, receptor-binding domains and internal repeats of human apolipoprotein B-100. Nature. 1986;323:738–42.

    Article  CAS  PubMed  Google Scholar 

  92. Yoshimoto R, Fujita Y, Kakino A, et al. The discovery of LOX-1, its ligands and clinical significance. Cardiovasc Drugs Ther. 2011;25:379–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Chang PY, Chen YJ, Chang FH, et al. Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction. Cardiovasc Res. 2013;99:137–45.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Our work described in this review was supported in part by grants from the American Diabetes Association (1-04-RA-13), the National Heart, Lung, and Blood Institute (HL-63364), Merck/Schering-Plough Pharmaceuticals (research grant), the Mao-Kuei Lin Research Fund of Chicony Electronics, the National Science Council (NSC 100-2314-B-039-040-MY3), and Kaohsiung Medical University Hospital, Taiwan (research grant 101-KMUH-M047).

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Liang-Yin Ke, Nicole Stancel, Henry Bair, and Chu-Huang Chen declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Chu-Huang Chen.

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Liang-Yin Ke and Nicole Stancel contributed equally to the article.

This article is part of the Topical Collection on Genetics

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Ke, LY., Stancel, N., Bair, H. et al. The Underlying Chemistry of Electronegative LDL’s Atherogenicity. Curr Atheroscler Rep 16, 428 (2014). https://doi.org/10.1007/s11883-014-0428-y

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