Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor

We have shown previously that human apolipoprotein (apo)C1 transgenic mice exhibit hyperlipidaemia, due primarily to an impaired clearance of very-low -density lipoprotein (VLDL) particles from the circulation. In the absence of at least the low-density-lipoprotein receptor (LDLR), it was shown that APOC1 overexpression in transgenic mice inhibited the hepatic uptake of VLD L via the LDLR-related protein. In the present study, we have now examined the effect of apoC1 on the binding of lipoproteins to both the VLDL recepto r (VLDLR) and the LDLR, The binding specificity of the VLDLR and LDLR for a poC1-enriched lipoprotein particles was examined in vivo through adenovirus -mediated gene transfer of the VLDLR and the LDLR [giving rise to adenoviru s-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOC1 transgenic mice, LDLR-deficient (LDLR-/-) mice and wild-type mice, Remarkably, Ad-VLDLR tre atment did not reduce hyperlipidaemia in transgenic mice overexpressing hum an APOC1, irrespective of both the level of transgenic expression and the p resence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR-/- and wild-type mice. On the other hand, Ad-LDLR treatment strong ly decreased plasma lipid levels in these APOC1 transgenic mice. These resu lts suggest that apoC1 inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitr o binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR ( CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOC1 transgenic VLDL than wild-ty pe VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependen tly the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), wherea s apoE did not enhance the binding of APOC1 transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOC1 trans genic VLDL were stimulated upon enrichment with apoE. From these studies, w e conclude that apoC1 specifically inhibits the apoE-mediated binding of tr iacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoC1-enrich ed lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoC1-containing lipoprotein particles p rovides further evidence for a regulatory role of apoC1 in the delivery of lipoprotein constituents to different tissues on which these receptors are located.