An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins

We have used adenovirus-mediated gene transfer in mice to investigate low d ensity lipoprotein receptor (LDLR) and LDLR-related protein (LRP)-independe nt mechanisms that control the metabolism of chylomicron and very low densi ty lipoprotein (VLDL) remnants in vivo. Overexpression of receptor-associat ed protein (RAP) in mice that lack both LRP and LDLR (MX1cre(+)LRP(flox/flo x)LDLR(-/-)) in their livers elicited a marked hypertriglyceridemia in addi tion to the pre-existing hypercholesterolemia in these animals, resulting i n a shift in the distribution of plasma lipids from LDL-sized lipoproteins to large VLDL-sized particles. This dramatic increase in plasma lipids was not due to a RAP-mediated inhibition of a unknown hepatic high affinity bin ding site involved in lipoprotein metabolism, because no RAP binding could be detected in livers of MX1cre(+)LRP(flox/flox)LDLR(-/-) mice using both m embrane binding studies and ligand blotting experiments. Remarkably, RAP ov erexpression also resulted in a 7-fold increase (from 13.6 to 95.6 ng/ml) o f circulating, but largely inactive, lipoprotein lipase (LPL), In contrast, plasma hepatic lipase levels and activity were unaffected. In vitro studie s showed that RAP binds to LPL with high affinity (K-d = 5 nM) but does not affect its catalytic activity, in vitro or in vivo. Our findings suggest t hat an extrahepatic RAP-sensitive process that is independent of the LDLR o r LRP is involved in metabolism of triglyceride-rich lipoproteins. There, R AP may affect the functional maturation of LPL, thus causing the accumulati on of triglyceride-rich lipoproteins in the circulation.