TRANSGENIC MICE CARRYING THE APOLIPOPROTEIN-E3-LEIDEN GENE EXHIBIT HYPERLIPOPROTEINEMIA

Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of familial dysbetalipopro teinemia. To study the effect of the APOE3-Leiden mutation in vivo, t ransgenic mice were generated using a genomic 27-kilobase DNA construc t isolated from the APOE3-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 generat ed that showed human APOE and APOC1 expression. All strains had signif icantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic ch olesterol-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)-size d fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, whil e in mice kept on a regular diet, apoE3-Leiden protein was mainly asso ciated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE3-Leiden-expressing transgenic mice supports our finding t hat the apoE3-Leiden variant behaves like a dominant trait in the expr ession of familial dysbetalipoproteinemia. ApoE3-Leiden transgenic mic e 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.