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Journal of Lipid Research, Vol. 49, 1048-1055, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

Gery Gerritsen^*, Caroline C. van der Hoogt^,, Frank G. Schaap^**, Peter J. Voshol^,, Kyriakos E. Kypreos^*,, Nobuyo Maeda, Albert K. Groen^**, Louis M. Havekes^,,***, Patrick C. N. Rensen^, and Ko Willems van Dijk^1,*,

^* Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
^** Amsterdam Medical Center Liver Center, Amsterdam, The Netherlands
Boston University School of Medicine, Boston, MA
Department of Pathology, University of North Carolina, Chapel Hill, NC
^*** Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

^* This research was conducted in the framework of the Leiden Center for Cardiovascular Research Leiden University Medical Center-TNO and supported by the Netherlands Heart Foundation (Project 2000.099), the Leiden University Medical Center (Gisela Thier Fellowship to P.C.N.R.), the Netherlands Organization for Scientific Research (NWO VIDI Grant 917.36.351 to P.C.N.R. and Netherlands Organization for Scientific Research Program Grant 903-39-291 to L.M.H.), the American Heart Association (Grant SDG 0535443T to K.E.K.), and the National Institutes of Health (Grant HL-42630 to N.M.).

Published, JLR Papers in Press, February 10, 2008.

¹ To whom correspondence should be addressed. e-mail: kowvd{at}lumc.nl

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 investigated whether direct or indirect stimulation of LPL activity in vivo reduces the apoE2-associated hypertriglyceridemia. 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 hypertriglyceridemia 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. 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.

Supplementary key words apolipoprotein E2 • apolipoprotein A-V • apolipoprotein C-III • APOE2-knockin mice • lipoprotein lipase-mediated very low density lipoprotein-triglyceride hydrolysis • adenovirus-mediated gene transfer

Abbreviations: apoE2, apolipoprotein E2; FPLC, fast-protein liquid chromatography; HSPG, heparan sulfate proteoglycan; TC, total cholesterol; TG, triglyceride

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