ApoCIII-Enriched LDL in Type 2 Diabetes Displays Altered Lipid Composition, Increased Susceptibility for Sphingomyelinase, and Increased Binding to Biglycan

Abstract

OBJECTIVEApolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. We investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes.RESEARCH DESIGN AND METHODSLDL was isolated from control subjects, subjects with type 2 diabetes, and apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [3H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms.RESULTSWe showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII are responsible for further increased proteoglycan binding of diabetic LDL with high-endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by sphingomyelinases. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content and that sialylation of apoCIII was essential for its proinflammatory properties.CONCLUSIONSWe have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.

Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes

“…apoC-III proteoforms show substantial functional differences in regulating cellular VLDL uptake in vitro (25). The few small studies in humans also indicate distinct effects of major apoC-III proteoforms on metabolic phenotypes (12,22,26). The scarcity of available data characterizing relationships between apoC-III proteoforms and human lipid phenotypes is partly explained by the limitations of using the relatively labor intensive isoelectric focusing approach for studies in larger cohorts.…”

“…LDL cholesterol was calculated their retention in the vascular wall, and stimulates production of inflammatory cytokines and adhesion molecules in monocytes and endothelial cells (11)(12)(13). In humans, higher apoC-III concentrations on lipoprotein particles are associated with both atherosclerosis progression and incident coronary artery disease (14)(15)(16)(17).…”

Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes

“…ApoCIII is known to be an important link between glycaemia and dyslipidaemia [22] as its expression is induced by high glucose levels and is responsive to insulin. However, whilst several studies have shown that higher apoCIII content on lipoproteins is associated with their atherogenicity [23,24], the association of total circulating apoCIII itself with CVD has had less investigation [21]. One of the largest studies is the Hoorn study [25].…”

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

“…Studies have shown that sphingomyelinase (SMase) activity is elevated in the serum of patients with type 2 diabetes [24], and also that LDL isolated from type 2 diabetic individuals is enriched with the SMase activator ApoC-III [25]. Depletion of cell-surface SM with SMase results in a simultaneous loss of FC [26], and thus increased SMase activity will result in parallel decreases in SM and FC.…”