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OBJECTIVE Apolipoprotein 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 METHODS LDL 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. RESULTS We 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. CONCLUSIONS We 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.

In response to increases in fat mass, as seen in obesity, the adipose tissue undergoes distinct structural remodeling (1). Recent attention has focused on the importance of the extracellular matrix (ECM) in remodeling of adipose tissue during the development of obesity. The ECM not only provides structural support to the surrounding cells, but also plays a crucial role in the biological function of different organs. Components of the ECM include structural proteins, such as collagen and fibrillins, and various classes of adhesion proteins, such as fibronectin and proteoglycan. Fibrillins are large proteins that form extracellular microfibril suprastructures ubiquitously found in elastic and nonelastic tissues. Constitutive components of the microfibrils also include the microfibril-associated glycoproteins (MAGPs) 1 and 2 (2,3). Microfibrils appear to have dual roles: They confer mechanical stability and limited elasticity to tissues and modulate the activity of members of the transforming growth factor-β (TGF-β) superfamily (4–6). The importance of microfibrils in regulating TGF-β activity is illustrated by the phenotype associated …