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)Cl 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 APOCI overexpression in transgenic mice inhibited the hepatic uptake of VLDL via the LDLR-related protein. In the present study, we have now examined the effect of apoCl on the binding of lipoproteins to both the VLDL receptor (VLDLR) and the LDLR. The binding specificity of the VLDLR and LDLR for apoCl-enriched lipoprotein particles was examined in vitro through adenovirus-mediated gene transfer of the VLDLR and the LDLR [giving rise to adenovirus-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOCI transgenic mice, LDLR-deficient (LDLR(-/-)) mice and wild-type mice. Remarkably, Ad-VLDLR treatment did not reduce hyperlipidaemia in transgenic mice overexpressing human APOCI, irrespective of both the level of transgenic expression and the presence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR(-/-) and wild-type mice. On the other hand, Ad-LDLR treatment strongly decreased plasma lipid levels in these APOCI transgenic mice. These results suggest that apoCl inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitro binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR (CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOCI transgenic VLDL than wild-type VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependently the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), whereas apoE did not enhance the binding of APOCI transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOCI transgenic VLDL were stimulated upon enrichment with apoE. From these studies, we conclude that apoCl specifically inhibits the apoE-mediated binding of triacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoCl-enriched lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoCl-containing lipoprotein particles provides further evidence for a regulatory role of apoCl in the delivery of lipoprotein constituents to different tissues on which these receptors are located.