Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis

The differential effects of overexpression of human apolipoprotein (apo) E3 on plasma cholesterol and triglyceride metabolism were investigated in tra nsgenic rabbits expressing low (10 mg/dL), medium (10 to 20 mg/dL), or high (>20 mg/dL) levels of apoE3. Cholesterol levels increased progressively wi th increasing levels of apoE3, whereas triglyceride levels were not signifi cantly affected at apoE3 levels up to 20 mg/dL but were markedly increased at levels of apoE3 >20 mg/dL. The medium expressers had marked hypercholest erolemia (up to 3- to 4-fold over nontransgenics), characterized by an incr ease in low density lipoprotein (LDL) cholesterol, while the low expressers had only slightly increased plasma cholesterol levels. The medium expresse rs displayed an 18-fold increase in LDL but also had a 2-fold increase in h epatic very low density lipoprotein (VLDL) triglyceride production, an 8-fo ld increase in VLDL apoB, and a moderate decrease in the ability of the VLD L to be lipolyzed. However, plasma clearance of VLDL was increased, likely because of the increased apoE3 content. The increase in LDL appears to be d ue to an enhanced competition of VLDL for LDL receptor binding and uptake, resulting in the accumulation of LDL. The combined hyperlipidemia of the ap oE3 high expressers (>20 mg/dL) was characterized by a 19-fold increase in LDL cholesterol but also a 4-fold increase in hepatic VLDL triglyceride pro duction associated with a marked elevation of plasma VLDL triglycerides, ch olesterol, and apoB 100 (4-, 9-, and 25-fold over nontransgenics, respectiv ely). The VLDL from the high expressers was much more enriched in apoE3 and markedly depleted in apoC-II, which contributed to a >60% inhibition of VL DL lipolysis. The combined effects of stimulated VLDL production and impair ed VLDL Lipolysis accounted for the increases in plasma triglyceride and VL DL concentrations in the apoE3 high expressers. The hyperlipidemic apoE3 ra bbits have phenotypes similar to those of familial combined hyperlipidemia, in which VLDL overproduction is a major biochemical feature. Overall, elev ated expression of apoE3 appears to determine plasma lipid levels by stimul ating hepatic VLDL production, enhancing VLDL clearance, and inhibiting VLD L lipolysis. Thus, the differential expression of apoE may, within a rather narrow range of concentrations, play a critical role in modulating plasma cholesterol and triglyceride levels and may represent an important determin ant of specific types of hyperlipoproteinemia.