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 the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes (Apoe-/- · Ldlr-/-) using adenovirus-mediated gene transfer. We found that a low level of APOE expression, that was capable of reducing the hyperlipidemia in Apoe-/- mice, did not result in a reduction of the hyperlipidemia in Apoe- /- · Ldlr-/- mice. Surprisingly, a very high level of APOE expression also did not result in a reduction of hypercholesterolemia in Apoe-/- · Ldlr- /mice, despite very high levels of circulating apoE (≥160 mg/dl). Only a moderately high level of APOE expression resulted in a reduction of serum cholesterol 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 resulted in a severe hypertriglyceridemia in Apoe-/- · Ldlr-/- mice and not Apoe-/- mice (25.7 ± 8.9 and 2.2 ± 1.8 mmol/l, respectively). This hypertriglyceridemia was associated with an APOE-induced increase in the VLDL triglyceride production rate and an inhibition of VLDL-triglyceride lipolysis. We conclude from these data that, for efficient clearance, the non-LDL receptor-mediated pathway requires a higher level of APOE expression as compared to the LDL receptor, but is more sensitive to an APOE-induced increase in VLDL production and inhibition of VLDL-triglyceride lipolysis. Chemicals/CAS: cholesterol, 57-88-5; Apolipoproteins E; Cholesterol, 57-88-5; Lipoprotein Lipase, EC 3.1.1.34; Lipoproteins; Lipoproteins, VLDL; Receptors, LDL; Triglycerides; very low density lipoprotein triglyceride