Hyperlipidemia of ApoE2(Arg 158 -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

Abstract

Abstract —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 transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes ( Apoe−/−.Ldlr−/− mice). Unexpectedly, on the Apoe−/−.Ldlr−/− background, expression of neither apoE2 nor apoE3-Leiden results in a decrease of the hyperlipidemia. In contrast, serum cholesterol levels are increased by the introduction of apoE2 and apoE3-Leiden in Apoe−/−.Ldlr−/− mice (to 39.1±7.1 and 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 increased (to 9.6±7.0 and 5.8±2.8 mmol/L, respectively, from 0.7±0.5 mmol/L), which is associated with a decreased efficiency of in vitro LPL-mediated 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 receptor, clearance of triglyceride-rich apoE2 and apoE3-Leiden–containing lipoproteins via alternative hepatic receptors, such as the LDL receptor–related protein (LRP) is inefficient. Although apoE2 and apoE3-Leiden are disturbed 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, overexpression of the LDL receptor via adenovirus-mediated gene transfer rescues the hyperlipidemia associated with apoE2 and apoE3-Leiden expression. These data indicate that in apoE2 and apoE3-Leiden transgenic mice, the LDL receptor constitutes the predominant route for clearance of VLDL remnants, carrying even poorly binding apoE variants, and that this pathway is functional despite an apoE-mediated disturbance in VLDL triglyceride lipolysis.