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Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2945-2951

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2945.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hyperlipidemia of ApoE2(Arg158-Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

Ko Willems van Dijk; Bart J.M. van Vlijmen; Menno P.J. de Winther; Belinda van ’t Hof; Andre van der Zee; Hans van der Boom; Louis M. Havekes; Marten H. Hofker

From the Department of Human Genetics (K.W.v.D., M.P.J.d.W., A.v.d.Z., M.H.H.) and the Departments of Cardiology and Internal Medicine (L.M.H.), Leiden University Medical Center, and TNO Prevention and Health, Gaubius Laboratory (B.J.M.v.V., B.v.t.H., H.v.d.B., L.M.H.), Leiden, The Netherlands.

Correspondence to Dr K. Willems van Dijk, Department of Human Genetics, Leiden University Medical Center, PO Box 9503, 2300 RA Leiden, The Netherlands. E-mail ko{at}ruly46.medfac.leidenuniv.nl

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(Arg158-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.


Key Words: apolipoprotein E • LDL receptor • LDL receptor–related protein • hypertriglyceridemia • VLDL triglyceride lipolysis




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