Journal Article

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

Carreira, Erick, Krützfeldt, Jan, Wollscheid, Bernd, Yalcinkaya, Mustafa, von Eckardstein, Arnold, Beerenwinkel, Niko, Wolfrum, Christian, Kränkel, Nicolle, Hornemann, Thorsten, Goetze, Sandra, Liebisch, Gerhard, Landmesser, Ulf, Rohrer, Lucia, Luca, Edlira, Hunjadi, Monika, Radosavljevic, Silvija, Keel, Michaela, Hartung, Johannes, Ritsch, Andreas, Othman, Alaa, Claassen, Manfred, Shemet, Andrej, Cardner, Mathias, Balaz, Miroslav, Karsai, Gergely

2020

Overview

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 HDL, 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.

• Publisher: American Society for Clinical Investigation
• Subject: Adipocytes / Apolipoproteins / Apoptosis / Atherosclerosis / Biological Assay / Cardiovascular disease / Cholesterol / Coronary artery disease / Coronary Disease - metabolism / Diabetes / Diabetes mellitus / Diabetes Mellitus - metabolism / Diabetes Mellitus, Type 2 - metabolism / Endothelial cells / Glycosylphosphatidylinositol / Heart diseases / High density lipoprotein / Humans / Lipid composition / Lipidomics / Lipids / Lipoproteins / Lipoproteins - metabolism / Lipoproteins, HDL - chemistry / Lipoproteins, HDL - metabolism / Male / Mass spectrometry / Metabolism / NMR / Nuclear magnetic resonance / Phospholipase D1 / Physiology / Protein composition / Proteins / Proteomics / Respiration / Scientific imaging / Signal transduction / Size distribution / Sphingomyelin / Statistical models / Structure-Activity Relationship / Structure-function relationships