Structure-function relationships of HDL in diabetes and coronary heart disease

被引:90
作者
Cardner, Mathias [1 ,2 ]
Yalcinkaya, Mustafa [3 ,4 ]
Goetze, Sandra [5 ,6 ]
Luca, Edlira [4 ,7 ]
Balaz, Miroslav [5 ]
Hunjadi, Monika [8 ]
Hartung, Johannes [9 ]
Shemet, Andrej [10 ]
Kraenkel, Nicolle [9 ]
Radosavljevic, Silvija [3 ,4 ]
Keel, Michaela [3 ,4 ]
Othman, Alaa [3 ,4 ]
Karsai, Gergely [3 ,4 ]
Hornemann, Thorsten [3 ,4 ]
Claassen, Manfred [6 ,11 ]
Liebisch, Gerhard [12 ]
Carreira, Erick [10 ]
Ritsch, Andreas [8 ]
Landmesser, Ulf [9 ]
Kruetzfeldt, Jan [4 ,7 ]
Wolfrum, Christian [5 ]
Wollscheid, Bernd [5 ,6 ]
Beerenwinkel, Niko [1 ,2 ]
Rohrer, Lucia [3 ,4 ]
von Eckardstein, Arnold [3 ,4 ]
机构
[1] Swiss Fed Inst Technol, Swiss Fed Inst Technol Zurich, Dept Biosyst Sci & Engn, Basel, Switzerland
[2] Swiss Inst Bioinformat, Basel, Switzerland
[3] Univ Zurich, Inst Clin Chem, Zurich, Switzerland
[4] Univ Hosp Zurich, Zurich, Switzerland
[5] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Zurich, Switzerland
[6] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland
[7] Univ Zurich, Dept Diabetol & Endocrinol, Zurich, Switzerland
[8] Med Univ Innsbruck, Dept Internal Med, Innsbruck, Austria
[9] Univ Med Charite Berlin, Dept Cardiol, Berlin, Germany
[10] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Zurich, Switzerland
[11] Swiss Fed Inst Technol, Dept Biol, Zurich, Switzerland
[12] Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany
基金
瑞士国家科学基金会; 奥地利科学基金会;
关键词
HIGH-DENSITY-LIPOPROTEINS; CHOLESTEROL EFFLUX CAPACITY; TRANSFER INHIBITOR PROTEIN; HIGH-THROUGHPUT QUANTIFICATION; NUCLEAR-MAGNETIC-RESONANCE; MASS-SPECTROMETRY; ARTERY-DISEASE; APOA-IV; INSULIN-RESISTANCE; VARIABLE SELECTION;
D O I
10.1172/jci.insight.131491
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HU, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.
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页数:18
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