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Thromb Haemost 2014; 111(03): 518-530
DOI: 10.1160/TH13-02-0178
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism

Monireh Dashty
1   Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
,
Mohammad M. Motazacker
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Johannes Levels
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Marcel de Vries
1   Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Morteza Mahmoudi
4   Nanotechnology Research, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
5   Current Address: Department of Pediatrics, Division of Cardiology, School of Medicine, Stanford University, Stanford, California, USA
,
Maikel P. Peppelenbosch
2   Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
,
Farhad Rezaee
1   Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received: 28 February 2013

Accepted after major revision: 22 February 2013

Publication Date:
22 November 2017 (online)

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Summary

Apart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis from the site of synthesis to effector locations. To better understand the role of VLDL and LDL in the transport of proteins, we applied a combination of LTQ ORBITRAP-XL (nLC-MS/MS) with both in-SDS-PAGE gel and in-solution tryptic digestion of pure and defined VLDL and LDL fractions. We identified the presence of 95 VLDL-and 51 LDL-associated proteins including all known apolipoproteins and lipid transport proteins, and intriguingly a set of coagulation proteins, complement system and anti-microbial proteins. Prothrombin, protein S, fibrinogen γ, PLTP, CETP, CD14 and LBP were present on VLDL but not on LDL. Prenylcysteine oxidase 1, dermcidin, cathelicidin antimicrobial peptide, TFPI-1 and fibrinogen α chain were associated with both VLDL and LDL. Apo A-V is only present on VLDL and not on LDL. Collectively, this study provides a wealth of knowledge on the protein constituents of the human plasma lipoprotein system and strongly supports the notion that protein shuttling through this system is involved in the regulation of biological processes. Human diseases related to proteins carried by VLDL and LDL can be divided in three major categories: 1 – dyslipidaemia, 2 – atherosclerosis and vascular disease, and 3 – coagulation disorders.

Keywords

Proteomics - nLC-MS/MS - coagulation - prothrombin - protein S - TFPI-1 - atherothrombosis - LCAT - CETP - PLTP - apoAV - apolipoproteins - antimicrobial peptides - lysozyme C - dermicidin - lipopolysaccharide binding protein - CD14 - prenylcysteine oxidase - cathepcin D - nLC-MS/MS

 

  • References

  • 1 Alaupovic P. Apolipoprotein composition as the basis for classifying plasma lipoproteins. Characterization of ApoA- and ApoB-containing lipoprotein families. Prog Lipid Res 1991; 30: 105-138.
    CrossrefPubMedGoogle Scholar
  • 2 Campos H, Perlov D, Khoo C. et al. Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolaemia and hyper-triglyceridemia. J Lipid Res 2001; 42: 1239-1249.
    CrossrefPubMedGoogle Scholar
  • 3 Dashti M, Kulik W, Hoek F. et al. A phospholipidomic analysis of all defined human plasma lipoproteins. Sci Rep 2011; 1: 139.
    CrossrefPubMedGoogle Scholar
  • 4 Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982; 23: 97-104.
    CrossrefPubMedGoogle Scholar
  • 5 Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003; 144: 2201-2207.
    CrossrefPubMedGoogle Scholar
  • 6 Queiroz KC, Tio RA, Zeebregts CJ. et al. Human plasma very low density lipo-protein carries Indian hedgehog. J Proteome Res 2010; 9: 6052-6059.
    CrossrefPubMedGoogle Scholar
  • 7 Rezaee F, Casetta B, Levels JH. et al. Proteomic analysis of high-density lipoprotein. Proteomics 2006; 6: 721-730.
    CrossrefPubMedGoogle Scholar
  • 8 Fredrickson DS, Lees RS. A system for phenotyping hyperlipoproteinemia. Circulation 1965; 31: 321-327.
    CrossrefPubMedGoogle Scholar
  • 9 Thompson GR. Management of dyslipidaemia. Heart 2004; 90: 949-955.
    CrossrefPubMedGoogle Scholar
  • 10 Berliner JA, Heinecke JW. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 1996; 20: 707-727.
    CrossrefPubMedGoogle Scholar
  • 11 Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89: 331-340.
    CrossrefPubMedGoogle Scholar
  • 12 Lagrost L, Gambert P, Lallemant C. Combined Effects of Lipid Transfers and Li-polysis on Gradient Gel Patterns of Human Plasma LDL. Arterioscler Thromb Vasc Biol 1994; 14: 1327-1336.
    CrossrefPubMedGoogle Scholar
  • 13 Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res 2002; 43: 1997-2006.
    CrossrefPubMedGoogle Scholar
  • 14 Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998; 81: 7B-12B.
    CrossrefPubMedGoogle Scholar
  • 15 Sarwar N, Danesh J, Eiriksdottir G. et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007; 115: 450-458.
    CrossrefPubMedGoogle Scholar
  • 16 Adiels M, Olofsson SO, Taskinen MR. et al. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Ar-terioscler Thromb Vasc Biol 2008; 28: 1225-1236.
    CrossrefPubMedGoogle Scholar
  • 17 Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005; 96: 1221-1232.
    CrossrefPubMedGoogle Scholar
  • 18 Azzam KM, Fessler MB. Crosstalk between reverse cholesterol transport and innate immunity. Trends Endocrinol Metab 2012; 23: 169-178.
    CrossrefPubMedGoogle Scholar
  • 19 Willeit J, Kiechl S, Oberhollenzer F. et al. Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck Study. Arterioscler Thromb Vasc Biol 2000; 20: 529-537.
    CrossrefPubMedGoogle Scholar
  • 20 Moyer MP, Tracy RP, Tracy PB. et al. Plasma Lipoproteins Support Prothrombi-nase and Other Procoagulant Enzymatic Complexes. Arterioscler Thromb Vasc Biol 1998; 18: 458-465.
    CrossrefPubMedGoogle Scholar
  • 21 Rota S, McWilliam NA, Baglin TP. et al. Atherogenic Lipoproteins Support Assembly of the Prothrombinase Complex and Thrombin Generation: Modulation by Oxidation and Vitamin E. Blood 1998; 91: 508-515.
    CrossrefPubMedGoogle Scholar
  • 22 Griffin JH, Kojima K, Banka CL. et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103: 219-227.
    CrossrefPubMedGoogle Scholar
  • 23 Kleinveld HA, Duif PF, Pekelharing HL. et al. Oxidation of lipoprotein (a) and low density lipoprotein containing density gradient ultracentrifugation fractions. Biochim Biophys Acta 1996; 1303: 15-21.
    CrossrefPubMedGoogle Scholar
  • 24 Levels JH, Bleijlevens B, Rezaee F. et al. SELDI-TOF mass spectrometry of High-Density Lipoprotein. Proteome Sci 2007; 5: 15.
    CrossrefPubMedGoogle Scholar
  • 25 Cham BE, Knowles BR. A solvent system for delipidation of plasma or serum without protein precipitation. J Lipid Res 1976; 17: 176-181.
    CrossrefPubMedGoogle Scholar
  • 26 Meijer K, de Vries M, Al-Lahham S. et al. Human primary adipocytes exhibit immune cell function: adipocytes prime inflammation independent of macro-phages. PLoS One 2011; 6: e17154
    CrossrefPubMedGoogle Scholar
  • 27 Zhang J, Xin L, Shan B. et al. PEAKS DB: de novo sequencing assisted database search for sensitive and accurate peptide identification. Mol Cell Proteomics 2012; 11: M111010587
    CrossrefPubMedGoogle Scholar
  • 28 Xie C, Mao X, Huang J. et al. KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res 2011; 39: W316-W322.
    CrossrefPubMedGoogle Scholar
  • 29 Salvayre R, Auge N, Benoist H. et al. Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta 2002; 1585: 213-221.
    CrossrefPubMedGoogle Scholar
  • 30 Zapf S, Loos M. Effect of EDTA and citrate on the functional activity of the first component of complement, C1, and the C1q subcomponent. Immunobiology 1985; 170: 123-132.
    CrossrefPubMedGoogle Scholar
  • 31 Golanski J, Pietrucha T, Baj Z. et al. Molecular insights into the anticoagulant-induced spontaneous activation of platelets in whole blood-various anticoagulants are not equal. Thromb Res 1996; 83: 199-216.
    CrossrefPubMedGoogle Scholar
  • 32 Yang L, Manithody C, Rezaie AR. Heparin-activated antithrombin interacts with the autolysis loop of target coagulation proteases. Blood 2004; 10: 1753-1759.
    CrossrefPubMedGoogle Scholar
  • 33 Karlsson H, Leanderson P, Tagesson C. et al. Lipoproteomics I: mapping of proteins in low-density lipoprotein using two-dimensional gel electrophoresis and mass spectrometry. Proteomics 2005; 5: 551-565.
    CrossrefPubMedGoogle Scholar
  • 34 Mancone C, Amicone L, Fimia GM. et al. Proteomic analysis of human very low-density lipoprotein by two-dimensional gel electrophoresis and MALDI- TOF/TOF. Proteomics 2007; 7: 143-154.
    CrossrefPubMedGoogle Scholar
  • 35 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: 336-344.
    CrossrefPubMedGoogle Scholar
  • 36 Egusa G, Beltz WF, Grundy SM. et al. Influence of obesity on the metabolism of apolipoprotein B in humans. J Clin Invest 1985; 76: 596-603.
    CrossrefPubMedGoogle Scholar
  • 37 Fuhrman B, Volkova N, Aviram M. Paraoxonase 1 (PON1) is present in postprandial chylomicrons. Atherosclerosis 2005; 180: 55-61.
    CrossrefPubMedGoogle Scholar
  • 38 Deakin S, Moren X, James RW. Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells. Atherosclerosis 2005; 179: 17-25.
    CrossrefPubMedGoogle Scholar
  • 39 O’Brien PJ, Alborn WE, Sloan JH. et al. The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. Clin Chem 2005; 51: 351-359.
    CrossrefPubMedGoogle Scholar
  • 40 Wang X, Driscoll DM, Morton RE. Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F. J Biol Chem 1999; 274: 1814-1820.
    CrossrefPubMedGoogle Scholar
  • 41 Dennis MW, Downey C, Brufatto N. et al. Prothrombinase enhancement through quantitative and qualitative changes affecting very low density lipopro-tein in complex with C-reactive protein. Thromb Haemost 2004; 91: 522-530.
    Article in Thieme ConnectPubMedGoogle Scholar