ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan

Anne Hiukka, Marcus Ståhlman, Camilla Pettersson, Malin Levin, Martin Adiels, Susanne Teneberg, Eeva S. Leinonen, Lillemor Mattsson Hultén, Olov Wiklund, Matej Orešič, Sven-Olof Olofsson, Marja-Riitta Taskinen, Kim Ekroos, Jan Borén (Corresponding Author)

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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.

Original languageEnglish
Pages (from-to)2018-2026
JournalDiabetes
Volume58
Issue number9
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

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Biglycan
Apolipoprotein C-III
Sphingomyelin Phosphodiesterase
LDL Lipoproteins
Type 2 Diabetes Mellitus
Lipids
Proteoglycans
low density lipoprotein inhibitor
oxidized low density lipoprotein
Protein Isoforms
Hydrolysis
Sphingomyelins
Apolipoproteins B
Isoelectric Focusing

Cite this

Hiukka, Anne ; Ståhlman, Marcus ; Pettersson, Camilla ; Levin, Malin ; Adiels, Martin ; Teneberg, Susanne ; Leinonen, Eeva S. ; Mattsson Hultén, Lillemor ; Wiklund, Olov ; Orešič, Matej ; Olofsson, Sven-Olof ; Taskinen, Marja-Riitta ; Ekroos, Kim ; Borén, Jan. / ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan. In: Diabetes. 2009 ; Vol. 58, No. 9. pp. 2018-2026.
@article{2bb93c3ebd564334a4e7050f9141f99f,
title = "ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan",
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.",
author = "Anne Hiukka and Marcus St{\aa}hlman and Camilla Pettersson and Malin Levin and Martin Adiels and Susanne Teneberg and Leinonen, {Eeva S.} and {Mattsson Hult{\'e}n}, Lillemor and Olov Wiklund and Matej Orešič and Sven-Olof Olofsson and Marja-Riitta Taskinen and Kim Ekroos and Jan Bor{\'e}n",
year = "2009",
doi = "10.2337/db09-0206",
language = "English",
volume = "58",
pages = "2018--2026",
journal = "Diabetes",
issn = "0012-1797",
number = "9",

}

Hiukka, A, Ståhlman, M, Pettersson, C, Levin, M, Adiels, M, Teneberg, S, Leinonen, ES, Mattsson Hultén, L, Wiklund, O, Orešič, M, Olofsson, S-O, Taskinen, M-R, Ekroos, K & Borén, J 2009, 'ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan', Diabetes, vol. 58, no. 9, pp. 2018-2026. https://doi.org/10.2337/db09-0206

ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan. / Hiukka, Anne; Ståhlman, Marcus; Pettersson, Camilla; Levin, Malin; Adiels, Martin; Teneberg, Susanne; Leinonen, Eeva S.; Mattsson Hultén, Lillemor; Wiklund, Olov; Orešič, Matej; Olofsson, Sven-Olof; Taskinen, Marja-Riitta; Ekroos, Kim; Borén, Jan (Corresponding Author).

In: Diabetes, Vol. 58, No. 9, 2009, p. 2018-2026.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase and increased binding to biglycan

AU - Hiukka, Anne

AU - Ståhlman, Marcus

AU - Pettersson, Camilla

AU - Levin, Malin

AU - Adiels, Martin

AU - Teneberg, Susanne

AU - Leinonen, Eeva S.

AU - Mattsson Hultén, Lillemor

AU - Wiklund, Olov

AU - Orešič, Matej

AU - Olofsson, Sven-Olof

AU - Taskinen, Marja-Riitta

AU - Ekroos, Kim

AU - Borén, Jan

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.2337/db09-0206

DO - 10.2337/db09-0206

M3 - Article

VL - 58

SP - 2018

EP - 2026

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -