J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on May 1, 2008

Papers In Press, published online ahead of print February 10, 2008
J. Lipid Res., doi:10.1194/jlr.M800009-JLR200
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Submitted on January 8, 2008
Revised on January 31, 2008
Accepted on February 10, 2008

ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoAV, but unaffected by apoCIII-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

General Internal Medicine and Human Genetics, Leiden University Medical Center, Leiden 2333ZC

Corresponding Author: kowvd{at}lumc.nl

ApoE2-associated hyperlipidemia is characterized by a disturbed clearance of apoE2-enriched VLDL-remnants. Since excess apoE2 inhibits lipoprotein lipase (LPL)-mediated triglyceride (TG)-hydrolysis in-vitro, we investigated whether direct or indirect stimulation of LPL activity in-vivo reduces the apoE2-associated hypertriglyceridemia. Hereto, we studied the role of LPL and two potent modifiers, the LPL-inhibitor apoCIII and the LPL-activator apoAV 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 direct activation of LPL activity. Indirect activation of LPL via overexpression of apoAV does, whereas deletion of apoCIII does not affect the plasma triglycerides in APOE2 mice. These data indicate that changes in apoAV levels have a dominant effect over changes in apoCIII levels in the improvement of APOE2-associated hypertriglyceridemia.


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