Hyperlipidemia of ApoE2(Arg(158)-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression

To investigate the relative roles of the LDL receptor- and non-LDL receptor -mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg(158)-Cys) (apoE2) and apoE3-leiden transg enic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (A poe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-/-.Ldlr-/- background, expr ession of neither apoE2 nor apoE3-leiden results in a decrease of the hyper lipidemia. In contrast, serum cholesterol levels are increased by the intro duction of apoE2 and apoE3-leiden in Apoe-/-.Ldlr-/- mice (to 39.1+/-7.1 an d 37.6+/-7.6 mmol/L, respectively, from 25.9+/-6.5 mmol/L). In addition, in these transgenic mice, the serum triglyceride levels are substantially inc reased (to 9.6+/-7.0 and 5.8+/-2.8 mmol/L, respectively, from 0.7+/-0.5 mmo l/L), which is associated with a decreased efficiency of in vitro LPL-media ted lipolysis of circulating VLDL. The VLDL-triglyceride secretion rate is not affected by the expression of apoE2 or apoE3-leiden on the Apoe-/-.Ldlr -/- background. These results indicate that in the absence of the LDL recep tor, clearance of triglyceride-rich apoE2 and apoE3-Leiden-containing lipop roteins via alternative hepatic receptors, such as the LDL receptor-related protein (LRP) is inefficient. Although apoE2 and apoE3-leiden are disturbe d in binding to the LDL receptor in vitro, expression of 1 or 2 mouse Ldlr alleles in an apoE2.Apoe-/-- or apoE3-Leiden.Apoe-/- background results in a gene dose-dependent decrease of the hyperlipidemia. Furthermore, overexpr ession of the LDL receptor via adenovirus-mediated gene transfer rescues th e hyperlipidemia associated with apoE2 and apoE3-leiden expression. These d ata indicate that in apoE2 and apoE3-leiden transgenic mice, the LDL recept or constitutes the predominant route for clearance of VLDL remnants, carryi ng even poorly binding apoE variants, and that this pathway is functional d espite an apoE-mediated disturbance in VLDL triglyceride lipolysis.