We have previously reported that Fab fragments of IgGs modified by lactosamination (lac-Fab) can direct macromolecules, including low density lipoproteins (LDL), to the liver. In the present paper we demonstrate that lac-Fab that is specific for LDL is an effective and selective hypolipoprotein agent. A plasma pool of about 60 mg/dl of apoprotein B (apo B) was induced in rats by bolus injection of human LDL (hLDL), which increased the cholesterol value to about 150 mg/dl. Three hours after injection of the highest dose of lac-Fab, the total cholesterol decreased to 80 mg/dl, compared to 120 mg/dl in control animals. Studies conducted with 131I-tyramine-cellobiose-labeled LDL indicated that the liver was the only organ in which lac-Fab increased LDL uptake and degradation. The effect of lac-Fab was dose-dependent. With amounts of lac-Fab between 13 to 42 mg/kg body weight, the amount of hLDL cleared through the lac-Fab mechanism ranged from 30% to 70% of the initial pool. Analysis of the plasma lipoprotein subfractions revealed that high density lipoprotein levels were not affected. Histologic examination of liver sections after sequential injection of fluorescently labeled hLDL and lac-Fab indicated specific uptake in the hepatocytes when compared to control sections obtained from animals injected with Dil-LDL alone. The uptake of fluorescent LDL induced by lac-Fab was completely prevented by a co-injection of an excess of asialofetuin. We conclude that lac-Fab that is specific for LDL is a selective hypolipoproteinemic agent and a specific carrier to the hepatocytes.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine