LDL receptor deficiency or ApoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice

Kyriakos E. Kypreos and Vassilis I. Zannis

Dept. of Molecular Genetics, Boston University School of Medicine, Boston, MA 02118-2394

Corresponding Author: vzannis{at}bu.edu

We have used adenovirus-mediated gene transfer and bolus injection of purified apoE in mice to determine the contribution of LDL-receptor family members in the clearance of apoE-containing lipoproteins in vivo, and the factors which trigger hypertriglyceridemia. A low dose (5x108 pfu) of an adenovirus expressing apoE4 did not normalize plasma cholesterol levels of apoE-/-xLDLr-/- mice and induced hypertriglyceridemia. A similar phenotype of combined dyslipidemia was induced in apoE-/- or apoE-/-xLDLr-/- mice following infection with a low dose (4x108pfu) of an adenovirus expressing the apoE4[R142V/R145V] mutant previously shown to be defective in receptor binding. In contrast, a low dose of 5x108 pfu of the apoE4-expressing adenovirus corrected hypercholesterolemia in apoE-/- mice and did not trigger hypertriglyceridemia. Bolus injection of purified apoE in apoE-/-xLDLr-/- 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. The 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.

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