Effect of the 39-kDa receptor-associated protein on the hepatic uptake and endocytosis of chylomicron remnants and low density lipoproteins in the rat

Hiroshi Mokuno, Sandra Brady, Leila Kotite, Joachim Herz, Richard J. Havel

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13238-13243
Number of pages6
JournalJournal of Biological Chemistry
Volume269
Issue number18
StatePublished - May 6 1994

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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