Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome

Abstract

OBJECTIVEBiochemical heterogeneity governs functional disparities among lipoproteins. We examined charge-defined VLDL subfractions in metabolic syndrome (MetS) to determine whether their increased electronegativity is associated with increased cytotoxicity and whether high concentrations of highly electronegative subfractions render VLDL harmful to the vascular endothelium.RESEARCH DESIGN AND METHODSPlasma VLDL of normal individuals (control subjects) (n = 13) and of those with MetS (n = 13) was resolved into subfractions with increasing negative charge (V1–V5) by anion-exchange chromatography. Human aortic endothelial cells were treated with V1–V5 or unfractionated VLDL.RESULTSCompared with the control subjects, individuals with MetS had a significantly higher percentage of V5 VLDL (V5/VLDL%) (34 ± 20 vs. 39 ± 11%, respectively; P < 0.05) and plasma V5 concentration ([V5]) (5.5 ± 4.4 vs. 15.2 ± 8.5 mg/dL, respectively; P < 0.001). Apolipoprotein (apo)B100 levels decreased and apoC levels increased from V1 to V5, indicating that V5 is apoC-rich VLDL. Regression analyses of all 26 individuals showed that [V5] was positively correlated with total cholesterol (P = 0.016), triglyceride (P < 0.000001), and V5/VLDL% (P = 0.002). Fasting plasma glucose, but not waist circumference, exhibited a positive trend (P = 0.058); plasma HDL cholesterol exhibited a weak inverse trend (P = 0.138). V5 (10 μg/mL) induced apoptosis in ~50% of endothelial cells in 24 h. V5 was the most rapidly (<15 min) internalized subfraction and induced the production of reactive oxygen species (ROS) in endothelial cells after 20 min. Unfractionated MetS VLDL, but not control VLDL, also induced ROS production and endothelial cell apoptosis.CONCLUSIONSIn populations with increased risk of diabetes, the vascular endothelium is constantly exposed to VLDL that contains a high proportion of V5. The potential impact of V5-rich VLDL warrants further investigation.

VLDL from Metabolic Syndrome Individuals Enhanced Lipid Accumulation in Atria with Association of Susceptibility to Atrial Fibrillation

“…Patients with MetS or type 2 diabetes often have increased plasma levels of TG and TG-derived very low density lipoproteins (VLDL) [ 15 , 16 ]. We previously showed that a negatively charged subfraction of VLDL in MetS patients was most toxic to human vascular endothelial cells and that the negatively charged VLDL was richer in MetS than healthy controls [ 17 ]. Moreover, VLDL from patients with AF is more highly glycated and more oxidized [ 18 ].…”

Association of very Low-density Lipoprotein Cholesterol with All-cause and Cardiovascular Mortality in Peritoneal Dialysis

“…Adiels et al [39] and Gill et al [40] reported that in patients with metabolic syndrome or type 2 diabetes, insulin-resistant states and the loss of insulin-mediated suppression of apoB100 secretion lead to increased production of large VLDL-1 particles. Hypersecretion of large VLDL-1 particles, which contain more cholesterol, results in higher levels of remnant particles and small dense LDLs and lower levels of HDL that may contribute to the progression of vascular endothelial injury and atherosclerosis [41-43]. In peritoneal dialysis, glucose absorption and protein loss from the dialysate further aggravate the metabolic abnormalities and insulin resistance.…”

The Pathogenic Role of Very Low Density Lipoprotein on Atrial Remodeling in the Metabolic Syndrome

“…From evaluating individuals with and without MetS, our colleagues reported the diversity of VLDLs, in which VLDL of MetS carries a more negative charge and is significantly cytotoxic to human vascular endothelial cells when compared with VLDL of non-MetS subjects [80]. Later we showed that VLDL of MetS patients induced cytosolic oxidative stress and exhibited more cytotoxicity to atrial myocytes (HL-1 cells) compared with VLDL of non-MetS subjects [81].…”