Uptake of lactoferrin by the liver. III. Critical role of the protein moiety.
Three possible modes of recognition of human lactoferrin (Lf), which is avidly taken up by the mouse liver, were examined. First, Lf has terminal galactosyl residues for which a receptor exists on hepatocytes. However, when large amounts of Lf were injected with 125I-asialoorosomucoid, no inhibition of asialoorosomucoid uptake by the liver was observed. Second, Lf that exposes fucosyl residues could be recognized by the sugar-polyspecific receptor of liver sinusoidal cells. Digestion of Lf by fucosidase did not affect considerably the uptake of Lf. In addition, bovine Lf, which lacks fucosyl residues, was also avidly taken up by the liver, and this uptake was inhibited by human Lf. Mannan and horseradish peroxidase, which are recognized by the sugar-polyspecific receptor, did not inhibit Lf uptake. These data demonstrate that galactosyl and fucosyl residues are not essential for Lf recognition. Third, Lf could be recognized by its protein moiety. To investigate this possibility, we used two Lf derivatives with intact carbohydrate side chains, carbamylated Lf and the C-terminal half molecule of Lf. Carbamylation reduced the uptake of Lf and its competitive activity toward the uptake of 125I-Lf. The C-terminal fragment, like carbamylated Lf, had a much weaker competitive activity than intact Lf. Therefore, the integrity of the protein moiety of Lf was required for its effective uptake by the liver. As Lf is a cationic protein, competition experiments were also done with lysozyme, another cationic protein which in the form of dimer is taken up by the liver reticuloendothelial system. The strong inhibition by dimerized lysozyme suggests that the liver reticuloendothelial system has common binding sites for certain cationic proteins, as recently shown for isolated macrophages.
D000818:Animals; D001212:Asialoglycoproteins; D001665:Binding Sites; D001667:Binding, Competitive; D002412:Cations / Q000378:metabolism; D002417:Cattle; D004705:Endocytosis; D004912:Erythrocytes / Q000378:metabolism; D005643:Fucose / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D006041:Goats; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism*; D007782:Lactoglobulins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008351:Mannans / Q000378:metabolism; D051379:Mice; D012157:Mononuclear Phagocyte System / Q000378:metabolism; D009113:Muramidase / Q000378:metabolism; D009961:Orosomucoid / Q000031:analogs & derivatives / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D005644:alpha-L-Fucosidase / Q000378:metabolism
D001212:Asialoglycoproteins; D002412:Cations; D007782:Lactoglobulins; D008351:Mannans; D009961:Orosomucoid; D011956:Receptors, Cell Surface; C017030:asialoorosomucoid; C038340:lactoferrin receptors; D005643:Fucose; D006735:Horseradish Peroxidase; D012259:Ribonuclease, Pancreatic; D009113:Muramidase; D005644:alpha-L-Fucosidase; D007781:Lactoferrin; D005690:Galactose