Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia

Abstract

Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of familial dysbetalipoproteinemia. To study the effect of the APOE*3-Leiden mutation in vivo, transgenic mice were generated using a genomic 27-kilobase DNA construct isolated from the APOE*3-Leiden proband. This construct carried the APOE gene, the APOC1 gene, and all known regulatory elements including an element that mediates liver expression. Three strains were generated that showed human APOE and APOC1 expression. All strains had significantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic cholesterol-rich diet, total plasma cholesterol and triglyceride levels increased dramatically. This increase was observed mainly in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-sized fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, while in mice kept on a regular diet, apoE3-Leiden protein was mainly associated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE*3-Leiden-expressing transgenic mice supports our finding that the apoE3-Leiden variant behaves like a dominant trait in the expression of familial dysbetalipoproteinemia. ApoE3-Leiden transgenic mice may serve as a model to elucidate additional factors involved in the metabolism of apoE containing remnant lipoproteins in general and the etiology of familial dysbetalipoproteinemia in particular.