Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells.
Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGE). Physiological aspects of the catabolism of non-enzymically glycated proteins were studied in vivo and in vitro. AGE-modified BSA (AGE-BSA) was a mixture of high-Mr (cross-linked), monomeric and low-Mr (fragmented) AGE-BSA. After intravenous administration in rat, all three fractions of AGE-BSA accumulated extremely rapidly and almost exclusively in liver. Uptake in liver endothelial, Kupffer and parenchymal cells accounted for approx. 60%, 25% and 10-15% respectively of hepatic elimination. Both cross-linked and monomeric AGE-BSA were efficiently taken up and degraded in cultures of purified liver endothelial and Kupffer cells. Endocytosis of AGE-BSA by these cells was inhibited by several ligands for the scavenger receptor. Although 125I-Hb was not endocytosed in vitro, 125I-AGE-Hb was effectively endocytosed by a mechanism that was subject to inhibition by AGE-BSA. Endocytosis of N-terminal propeptide of type I procollagen, a physiological ligand for the scavenger receptor, was effectively inhibited by AGE-Hb and AGE-BSA. We conclude that AGE-modification renders macromolecules susceptible for elimination via the scavenger receptor of both liver endothelial and Kupffer cells.
Smedsrød
B
B
Department of Experimental Pathology, University of Tromsø, Norway.
Melkko
J
J
Araki
N
N
Sano
H
H
Horiuchi
S
S
D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000493:pharmacokinetics*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B