REVERSAL OF HYPERCHOLESTEROLEMIA IN APOLIPOPROTEIN E2 AND APOLIPOPROTEIN E3-LEIDEN TRANSGENIC MICE BY ADENOVIRUS-MEDIATED GENE-TRANSFER OF THE VLDL RECEPTOR

We have investigated the interaction of apolipoprotein E2(Arg(158)-Cys ) (apoE2) and apolipoprotein E3Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define th e possible role of this receptor in lipoprotein metabolism and atheros clerosis. The in vivo binding specificity of the VLDL receptor for apo E2 and apoE3-Leiden was investigated by adenovirus-mediated gene trans fer of the VLDL receptor in apoE2 and apoE3-Leiden transgenic mice lac king endogenous mouse apoE (Apoe-/-). Ectopic overexpression of the VL DL receptor gene in the liver resulted in a >50% decrease of plasma ch olesterol levels in both apoE2 and apoE3-Leiden transgenic mice compar ed with liver expression of the beta-galactosidase gene. This reductio n in plasma cholesterol was mainly due to a reduction in the VLDL leve l. Overexpression of the VLDL receptor did not affect the hepatic VLDL triglyceride production, indicating that the hypocholesterolemic effe ct is due to an increased level of plasma clearance mediated by the VL DL receptor. In vitro binding analysis showed that both apoE2 and apoE 3-Leiden VLDL compete efficiently with rabbit beta-VLDL for binding to the VLDL receptor expressed on LDL receptor-deficient Chinese hamster ovary cells. We conclude from these data that both apoE2 and apoE3-Le iden function as proper ligands for the VLDL receptor in vitro and in vivo. This finding substantiates a possible role for the VLDL receptor in atherosclerosis in hyperlipidemic subjects homozygous for apoE2 or carrying apoE3-Leiden and indicates that the VLDL receptor expressed on the liver has therapeutic potential as an alternative route for cle arance of binding-defective lipoproteins.