In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE
TNO Preventie en Gezondheid
van Dijk, K.W.
van Vlijmen, B.J.M.
van 't Hof, H.B.
van der Zee, A.
van Berkel, T.J.C.
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 184.108.40.206; Lipoproteins; Lipoproteins, VLDL; Receptors, LDL; Triglycerides; very low density lipoprotein triglyceride
Adenovirus-mediated gene transfer
To reference this document use:
Hepatic VLDL triglyceride production
LDL receptor-related protein
Journal of Lipid Research, 40 (40), 336-344