Reversal of hypercholesterolemia in apolipoprotein E2 and apolipoprotein E3-Leiden transgenic mice by adenovirus-mediated gene transfer of the VLDL receptor

Arteriosclerosis, Thrombosis, and Vascular Biology
K W van DijkM H Hofker

Abstract

We have investigated the interaction of apolipoprotein E2(Arg158-Cys) (apoE2) and apolipoprotein E3-Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define the possible role of this receptor in lipoprotein metabolism and atherosclerosis. The in vivo binding specificity of the VLDL receptor for apoE2 and apoE3-Leiden was investigated by adenovirus-mediated gene transfer of the VLDL receptor in apoE2 and apoE3-Leiden transgenic mice lacking endogenous mouse apoE (Apoe-/-). Ectopic overexpression of the VLDL receptor gene in the liver resulted in a >50% decrease of plasma cholesterol levels in both apoE2 and apoE3-Leiden transgenic mice compared with liver expression of the beta-galactosidase gene. This reduction in plasma cholesterol was mainly due to a reduction in the VLDL level. Overexpression of the VLDL receptor did not affect the hepatic VLDL triglyceride production, indicating that the hypocholesterolemic effect is due to an increased level of plasma clearance mediated by the VLDL receptor. In vitro binding analysis showed that both apoE2 and apoE3-Leiden VLDL compete efficiently with rabbit beta-VLDL for binding to the VLDL receptor expressed on LDL receptor-deficient Chi...Continue Reading

References

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Citations

Dec 21, 2000·Current Atherosclerosis Reports·W J SchneiderM Drexler
Oct 8, 1999·Clinica Chimica Acta; International Journal of Clinical Chemistry·J DavignonL Bernier
May 16, 2001·Current Opinion in Lipidology·P J TackenK W van Dijk
Aug 17, 1999·Annual Review of Nutrition·M M HussainA Bakillah
May 20, 2003·Journal of Lipid Research·Dennis Van HoofDick J van der Horst
Sep 10, 2004·Journal of Atherosclerosis and Thrombosis·Sadao TakahashiTokuo T Yamamoto
May 28, 2003·Biochemical and Biophysical Research Communications·Thomas H FischerTimothy C Nichols
Sep 11, 1999·The Journal of Laboratory and Clinical Medicine·M Belalcazar, L Chan

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