ApoCIII-Enriched LDL in Type 2 Diabetes Displays Altered Lipid Composition, Increased Susceptibility for Sphingomyelinase, and Increased Binding to Biglycan
- Anne Hiukka1,
- Marcus Ståhlman2,
- Camilla Pettersson2,
- Malin Levin2,
- Martin Adiels2,
- Susanne Teneberg3,
- Eeva S. Leinonen1,
- Lillemor Mattsson Hultén2,
- Olov Wiklund2,
- Matej Orešič4,
- Sven-Olof Olofsson2,
- Marja-Riitta Taskinen1,
- Kim Ekroos5 and
- Jan Borén2
- 1Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland;
- 2Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden;
- 3Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden;
- 4Technical Research Centre of Finland VTT, Espoo, Finland;
- 5Zora Biosciences, Espoo, Finland.
- Corresponding author: Jan Borén, Jan.Boren{at}wlab.gu.se.
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A.H. and M.S. contributed equally to this study.
Abstract
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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received February 12, 2009.
- Accepted May 31, 2009.
- © 2009 by the American Diabetes Association.
