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.