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Originally published In Press as doi:10.1194/jlr.M500322-JLR200 on December 7, 2005

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Journal of Lipid Research, Vol. 47, 521-529, March 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in miceboxs

Kyriakos E. Kypreos and Vassilis I. Zannis1

Molecular Genetics, Departments of Medicine and Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118

boxs The online version of this article (available at http://www.jlr.org) contains additional figures.

Published, JLR Papers in Press, December 7, 2005.

1 To whom correspondence should be addressed. e-mail: vzannis{at}bu.edu

We have used adenovirus-mediated gene transfer and bolus injection of purified apolipoprotein E (apoE) in mice to determine the contribution of LDL receptor family members in the clearance of apoE-containing lipoproteins in vivo and the factors that trigger hypertriglyceridemia. A low dose [5 x 108 plaque-forming units (pfu)] of an adenovirus expressing apoE4 did not normalize plasma cholesterol levels of apolipoprotein E-deficient (apoE–/–) x low density lipoprotein receptor-deficient (LDLr–/–) mice and induced hypertriglyceridemia. A similar phenotype of combined dyslipidemia was induced in apoE–/– or apoE–/– x LDLr–/– mice after infection with a low dose (4 x 108 pfu) of an adenovirus expressing the apoE4[R142V/R145V] mutant previously shown to be defective in receptor binding. In contrast, a low dose of 5 x 108 pfu of the apoE4-expressing adenovirus corrected hypercholesterolemia in apoE–/– mice and did not trigger hypertriglyceridemia. Bolus injection of purified apoE in apoE–/– x LDLr–/– mice did not clear plasma cholesterol levels and induced mild hypertriglyceridemia. In contrast, similar injection of apoE in apoE–/– mice cleared plasma cholesterol and caused transiently mild hypertriglyceridemia. These findings suggest that a) the LDL receptor alone can account for the clearance of apoE-containing lipoproteins in mice, and the contribution of other receptors is minimal, and b) defects in either the LDL receptor or in apoE that affect its interactions with the LDL receptor, increase the sensitivity to apoE-induced hypertriglyceridemia in mice.

Supplementary key words apolipoprotein E • low density lipoprotein receptor • adenovirus-mediated gene transfer • bolus apolipoprotein E injection


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