TY - JOUR
T1 - Effect of the 39-kDa receptor-associated protein on the hepatic uptake and endocytosis of chylomicron remnants and low density lipoproteins in the rat
AU - Mokuno, Hiroshi
AU - Brady, Sandra
AU - Kotite, Leila
AU - Herz, Joachim
AU - Havel, Richard J.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/5/6
Y1 - 1994/5/6
N2 - The low density lipoprotein (LDL) receptor-related protein, which serves as the cell surface receptor for several proteins including α2- macroglobulin-protease complexes, has been proposed to be a candidate hepatocytic receptor for chylomicron remnants through its recognition of apolipoprotein E. We have studied the effect of two ligands for this receptor, activated α2-macroglobulin and the recently described 39-kDa protein that copurifies with the LDL receptor-related protein (receptor- associated protein), on the uptake and endocytosis of chylomicrons in intact rats and in isolated, perfused rat livers. Both of these ligands were rapidly taken up and endocytosed into the liver of rats. Chylomicrons from normal rats were injected in vivo and chylomicrons from estradiol-treated rats that were enriched in apolipoprotein E were added to liver perfusates. Prior administration of amounts of activated α2-macroglobulin that saturated hepatic uptake mechanisms did not inhibit hepatic uptake or endocytosis of endogenously labeled cholesteryl esters of chylomicron particles in vivo or in perfused livers over a period of 15 min. By contrast, prior administration of saturating amounts of the receptor-associated protein (expressed in bacteria as a fusion protein with glutathione S-transferase) reduced hepatic uptake by about 30% and virtually abolished endocytosis. The receptor- associated protein inhibited hepatic uptake of human LDL in vivo by 70% and endocytosis by 81%. Our results show that receptor-associated protein- sensitive processes predominate in the overall pathways by which chylomicron remnants are endocytosed by rat liver. Furthermore, they show that the receptor-associated protein binds to and inhibits the function of the LDL receptor as well as the LDL receptor-related protein.
AB - The low density lipoprotein (LDL) receptor-related protein, which serves as the cell surface receptor for several proteins including α2- macroglobulin-protease complexes, has been proposed to be a candidate hepatocytic receptor for chylomicron remnants through its recognition of apolipoprotein E. We have studied the effect of two ligands for this receptor, activated α2-macroglobulin and the recently described 39-kDa protein that copurifies with the LDL receptor-related protein (receptor- associated protein), on the uptake and endocytosis of chylomicrons in intact rats and in isolated, perfused rat livers. Both of these ligands were rapidly taken up and endocytosed into the liver of rats. Chylomicrons from normal rats were injected in vivo and chylomicrons from estradiol-treated rats that were enriched in apolipoprotein E were added to liver perfusates. Prior administration of amounts of activated α2-macroglobulin that saturated hepatic uptake mechanisms did not inhibit hepatic uptake or endocytosis of endogenously labeled cholesteryl esters of chylomicron particles in vivo or in perfused livers over a period of 15 min. By contrast, prior administration of saturating amounts of the receptor-associated protein (expressed in bacteria as a fusion protein with glutathione S-transferase) reduced hepatic uptake by about 30% and virtually abolished endocytosis. The receptor- associated protein inhibited hepatic uptake of human LDL in vivo by 70% and endocytosis by 81%. Our results show that receptor-associated protein- sensitive processes predominate in the overall pathways by which chylomicron remnants are endocytosed by rat liver. Furthermore, they show that the receptor-associated protein binds to and inhibits the function of the LDL receptor as well as the LDL receptor-related protein.
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M3 - Article
C2 - 7513700
AN - SCOPUS:0028284381
SN - 0021-9258
VL - 269
SP - 13238
EP - 13243
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -