INITIAL HEPATIC REMOVAL OF CHYLOMICRON REMNANTS IS UNAFFECTED BUT ENDOCYTOSIS IS DELAYED IN MICE LACKING THE LOW-DENSITY-LIPOPROTEIN RECEPTOR

Two endocytic receptors, the low density lipoprotein (LDL) receptor (L DLR) and the LDLR-related protein (LRP), are thought to act in concert in the hepatic uptake of partially metabolized dietary lipoproteins, the chylomicron remnants, We have evaluated the role of these two rece ptors in the hepatic metabolism of chylomicron remnants in normal mice and in LDLR-deficient [LDLR (-/-)] mice, The rate of chylomicron remn ant removal by the liver was normal up to 30 min after intravenous inj ection of chylomicrons into LDLR (-/-) mice and was unaffected by rece ptor-associated protein (RAP), a potent inhibitor of ligand binding to LRP. In contrast, endocytosis of the remnants by the hepatocytes, mea sured by their accumulation in the endosomal fraction and by the rate of hydrolysis of component cholesteryl esters, was dramatically reduce d in the absence of the LDLR. Coadministration of RAP prevented the co ntinuing hepatic removal of chylomicron remnants in LDL (-/-) mice aft er 30 min, consistent with blockade of the slow endocytosis by a RAP-s ensitive process, Taken together with previous studies, our results ar e consistent with a model in which the initial hepatic removal of chyl omicron remnants is primarily mediated by mechanisms that do not inclu de LDLR or LRP, possibly involving glycosaminoglycan-bound hepatic lip ase and apolipoprotein E. After the remnants bind to these alternative sites on the hepatocyte surface, endocytosis is predominantly mediate d by the LDLR and also by a slower and less efficient backup process t hat is RAP sensitive and therefore most likely involves LRP.