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ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency

Author: Gerritsen, G. · Hoogt, C.C. van der · Schaap, F.G. · Voshol, P.J. · Kypreos, K.E. · Maeda, N. · Groen, A.K. · Havekes, L.M. · Rensen, P.C.N. · Dijk, K.W. van
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 5, 49, 1048-1055
Identifier: 240787
doi: doi:10.1194/jlr.M800009-JLR200
Keywords: Health · Physiological Sciences · Adenovirus-mediated gene transfer · APOE2-knockin mice · Apolipoprotein A-V · Apolipoprotein C-III · Apolipoprotein E2 · Lipoprotein lipase-mediated very low density lipoprotein-triglyceride hydrolysis · apolipoprotein A · apolipoprotein A5 · apolipoprotein B · apolipoprotein C · apolipoprotein C3 · apolipoprotein D · apolipoprotein E · apolipoprotein M · beta2 glycoprotein 1 · clusterin · heparin · Apoa5 protein, mouse · apolipoprotein · Adenovirus · animal experiment · animal model · cholesterol blood level · conference paper · controlled study · disease association · female · gene overexpression · hypertriglyceridemia · in vivo study · lipoprotein deficiency · mouse · nonhuman · stimulation · triacylglycerol blood level · animal · blood · gene transfer · genetics · mouse mutant · physiology · Adenoviridae · Animals · Apolipoprotein C-III · Apolipoprotein E2 · Apolipoproteins · Gene Transfer Techniques · Hypertriglyceridemia · Lipids · Lipoprotein Lipase · Male · Mice · Mice, Knockout

Abstract

Apolipoprotein E2 (apoE2)-associated hyperlipidemia is characterized by a disturbed clearance of apoE2-enriched VLDL remnants. Because excess apoE2 inhibits LPL-mediated triglyceride (TG) hydrolysis in vitro, we in vestigated whether direct or indirect stimulation of LPL activity in vivo reduces the apoE2-associated hypertriglyc-eridemia. Here, we studied the role of LPL and two potent modifiers, the LPL inhibitor apoC-III and the LPL activator apoA-V, in APOE2-knockin (APOE2) mice. Injection of heparin in APOE2 mice reduced plasma TG by 53% and plasma total cholesterol (TC) by 18%. Adenovirus-mediated overexpression of LPL reduced plasma TG by 85% and TC by 40%. Both experiments indicate that the TG in apoE2-enriched particles is a suitable substrate for LPL. Indirect activation of LPL activity via deletion of Apoc3 in APOE2 mice did not affect plasma TG levels, whereas overexpression of Apoa5 in APOE2 mice did reduce plasma TG by 81% and plasma TC by 41%. In conclusion, the hypertriglyc-eridemia in APOE2 mice can be ameliorated by the direct activation of LPL activity. Indirect activation of LPL via overexpression of apoA-V does, whereas deletion of apoC-III does not, affect the plasma TGs in APOE2 mice.Qfl These data indicate that changes in apoA-V levels have a dominant effect over changes in apoC-III levels in the improvement of APOE2-associated hypertriglyceridemia. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.