Enhanced hepatic uptake and processing of cholesterol esters from low density lipoprotein by specific lactosaminated fab fragments

Martin K. Bijsterbosch, Franco Bernini, Hille F. Bakkeren, Antonio Gotto, Louis C. Smith, Theo J.C. Van Berkel

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Reduction of the blood levels of low density lipoprotein (LDL) is important for lowering the incidence of atherosclerosis. In this study, LDL was directed to rat parenchyma! liver cells by lactosantinated Fab fragments of anti-apolipoprotein B antibodies (LacFab). We followed the fate of intravenously injected complexes of LacFab and [3H] choiesterjl oleate-labeled LDL. Complexing of LacFab to LDL led to rapid disappearance of LDL from the circulation. At 30 minutes after injection, the liver contained 58.5±9.0% of the injected dose (at that time the liver contained only 5.7±2.2% of an injected dose of free LDL). Liver uptake was blocked by N-acetylgalactosamine but not by N-acetylglucosamine, which indicates that galactose-specific recognition sites are responsible for the LacFab-induced hepatic uptake. By isolating liver cells, it was found that parenchymal, endothelial, and Kupffer cells account for 87%, 3%, and 10% of the total hepatic uptake, respectively. Subcellular fractionation of the liver indicated that the complexes are rapidly internalized and transported to lysosomes. Within 1 hour after injection, virtually all the [3H]cholesteryl oleate of the internalized LDL was hydrolyzed; hydrolysis was followed by excretion of radioactivity into the bile. Compared with rats injected with native [3H]cholesteryl oleate-labeled LDL, eight times as much radioactivity was excreted into the bile during the first 4 hours after the injection of LacFab-complexed [3H] choiesteryl oleate-labeled LDL. Thus, LacFab induces enhanced hepatic uptake of LDL via galactose receptors on the parenchymal cells, followed by processing in lysosomes and excretion into the bile. In this way, LacFab induces an increased irreversible removal of LDL cholesterol from the body.

Original languageEnglish (US)
Pages (from-to)1806-1813
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume11
Issue number6
DOIs
StatePublished - 1991

Keywords

  • Bile excretion
  • Galactose receptor
  • Hypercholesterolemia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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