Transgenic mice were produced that expressed different plasma levels (3-60 mg/dl) of human apolipoprotein (apo) E2(Arg158 --> Cys), which is associated with the recessive form of human type III hyperlipoproteinemia (HLP). In transgenic mice fed a normal chow diet, low levels of apoE2 (<10 mg/dl) did not significantly alter the lipid phenotype. Mice expressing intermediate levels of apoE2 (10-30 mg/dl) had a 50-60% decrease in total cholesterol compared with nontransgenic mice. The decrease was almost entirely due to a reduction in high density lipoprotein (HDL) cholesterol. These hypolipidemic apoE2 transgenic mice were cross-bred with human apoB transgenic mice, which have increased total cholesterol and low density lipoprotein (LDL) levels. The apoE2/apoB double transgenics revealed that expression of apoE2 on the background of human apoB overexpression resulted in a substantial decrease in LDL and HDL cholesterol and a corresponding accumulation of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL). Thus, the double transgenics had a lipid phenotype resembling human type III HLP. In contrast to the hypolipidemic mice, mice expressing high levels of apoE2 (>50 mg/dl) were hyperlipidemic. The VLDL and IDL in these mice were significantly increased and cholesterol-enriched and had other characteristics of remnant lipoproteins. Upon agarose gel electrophoresis, the VLDL and IDL from both intermediate and high expressers migrated more slowly toward the beta position compared with the pre-beta-mobility of nontransgenic mouse VLDL and IDL. Thus, depending on plasma apoE2 levels, the expression of human apoE2 in the transgenic mice leads to either a hypolipidemic or hyperlipidemic phenotype. This animal model provides the opportunity to study the factors that cause hypolipidemia and those that precipitate the hyperlipidemia of type III HLP.