DIFFERENCES IN THE MECHANISMS OF UPTAKE AND ENDOCYTOSIS OF SMALL AND LARGE CHYLOMICRON REMNANTS BY RAT-LIVER

Initial binding and subsequent endocytosis of small and large chylomic ron remnants by rat Liver were compared, Small and large chylomicrons were obtained from mesenteric lymph of glucose- or fat-fed rats, respe ctively, The low-density lipoprotein (LDL) receptor was up- and down-r egulated as shown by LDL receptor messenger RNA (mRNA). The rate of re moval of small chylomicron remnants by isolated perfused rat livers fo llowed closely the activity of the LDL receptor, When mRNA was undetec table, the uptake was as low as that of lymphatic small chylomicrons, In contrast,the uptake of large chylomicron remnants into perfused rat livers was unaffected by changes of the LDL-receptor activity, but si gnificantly reduced after Livers were flushed with heparin or heparina se. Large chylomicron remnants were cleared from plasma much faster th an small chylomicron remnants, but were more slowly internalized into hepatocytes, Both, small and large chylomicron remnants entered the pa thway of receptor-mediated endocytosis as shown by electron microscopy and analysis of isolated endosomes, Yet, large chylomicron remnants w ere taken up into the compartment of uncoupling of receptors and ligan ds and multivesicular bodies at a much slower rate. This was independe nt of the activity of the LDL receptor and the heparin-releasable bind ing site. From these findings it is concluded that large chylomicron r emnants initially bind rapidly to surface components other than the LD L receptor, one of which may be hepatic lipase, Yet, the consecutive i nternalization is slow. In contrast, small chylomicron remnants are re moved at a slower rate from plasma, binding predominantly to the LDL r eceptor, but are more readily taken up into endosomes.