Increased APOE glycosylation plays a key role in the atherogenicity of L5 low-density lipoprotein.
Apolipoproteins E
/ chemistry
Apoptosis
Atherosclerosis
/ chemically induced
Case-Control Studies
Cells, Cultured
Endothelial Cells
/ drug effects
Glycosylation
Humans
Lipoproteins, LDL
/ adverse effects
Metabolic Syndrome
/ physiopathology
Molecular Docking Simulation
Protein Conformation
Protein Processing, Post-Translational
/ drug effects
Signal Transduction
APOE
L5 LDL
atherosclerosis
electronegative low-density lipoproteins
glycosylation
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
20
03
2020
revised:
19
05
2020
accepted:
20
05
2020
pubmed:
6
6
2020
medline:
2
3
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
Low-density lipoprotein (LDL) is heterogeneous, composed of particles with variable atherogenicity. Electronegative L5 LDL exhibits atherogenic properties in vitro and in vivo, and its levels are elevated in patients with increased cardiovascular risk. Apolipoprotein E (APOE) content is increased in L5, but what role APOE plays in L5 function remains unclear. Here, we characterized the contributions of APOE posttranslational modification to L5's atherogenicity. Using two-dimensional electrophoresis and liquid chromatography-mass spectrometry, we studied APOE's posttranslational modification in L5 from human plasma. APOE structures with various glycan residues were predicted. Molecular docking and molecular dynamics simulation were performed to examine the functional changes of APOE resulting from glycosylation. We also examined the effects of L5 deglycosylation on endothelial cell apoptosis. The glycan sequence N-acetylgalactosamine, galactose, and sialic acid was consistently expressed on serine 94, threonine 194, and threonine 289 of APOE in L5 and was predicted to contribute to L5's negative surface charge and hydrophilicity. The electrostatic force between the negatively charged sialic acid-containing glycan residue of APOE and positively charged amino acids at the receptor-binding area suggested that glycosylation interferes with APOE's attraction to receptors, lipid-binding ability, and lipid transportation and metabolism functions. Importantly, L5 containing glycosylated APOE induced apoptosis in cultured endothelial cells through lectin-like oxidized LDL receptor-1 (LOX-1) signaling, and glycosylation removal from L5 attenuated L5-induced apoptosis. APOE glycosylation may contribute to the atherogenicity of L5 and be a useful biomarker for rapidly quantifying L5.
Identifiants
pubmed: 32501643
doi: 10.1096/fj.202000659R
doi:
Substances chimiques
Apolipoproteins E
0
Lipoproteins, LDL
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9802-9813Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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