In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

To investigate the quantitative requirement for apolipoprotein (apo) E in t he clearance of lipoproteins via the non-low density lipoprotein (LDL) rece ptor mediated pathway, human APOE was overexpressed at various levels in th e livers of mice deficient for both the endogenous Apoe and Ldlr genes (Apo e-/-.Ldlr-/-) using adenovirus-mediated gene transfer. We found that a low level of APOE expression, that was capable of reducing the hyperlipidemia i n Apoe-/- mice, did not result in a reduction of the hyperlipidemia in Apoe -/-.Ldlr-/- mice. Surprisingly, a very high level of APOE expression also d id not result in a reduction of hypercholesterolemia in Apoe-/-.Ldlr-/- mic e, despite very high levels of circulating apoE (>160 mg/dl). Only a modera tely high level of APOE expression resulted in a reduction of serum cholest erol level (from 35.2 +/- 6.7 to 14.6 +/- 2.3 mmol/l) and the disappearance of VLDL from the serum. Moreover, the very high level of APOE expression r esulted in a severe hypertriglyceridemia in Apoe-/-.Ldlr-/- mice and not Ap oe-/- mice (25.7 +/- 8.9 and 2.2 +/- 1.8 mmol/l, respectively). This hypert riglyceridemia was associated with an APOE-induced increase in the VLDL tri glyceride production rate and an inhibition of VLDL-triglyceride lipolysis. We conclude from these data that, for efficient clearance, the non-LDL rec eptor-mediated pathway requires a higher level of APOE expression as compar ed to the LDL receptor, but is more sensitive to an APOE-induced increase i n VLDL production and inhibition of VLDL-triglyceride lipolysis.