The in vivo fate of /3-very low density lipoproteins (0-VLDLs) was investigated after Cu 2+ -mediated oxidative modification (Ox-0-VLDL). Ox-0-VLDL may be physiologically relevant under conditions of defective VLDL removal by the liver (type HI hyperlipoproteinemia) or overloading of the remnant receptor (high cholesterol feeding). On oxidation of /3 -VLDL, the kinetics of its removal from the blood and uptake by the liver are unchanged. However, in contrast to /3-VLDL, which is recognized by the remnant receptor of parenchymal cells, liver uptake of Ox-^-VLDL is mediated mainly by Kupffer cells (65% of liver-associated radioactivity). In vitro competition studies show that the cell association and degradation of iodine-125-labeled Ox-fi -VLDL by both liver endothelial and Kupffer cells are only marginally competed for by acetylated LDL (10-20%), while an efficient blockade is noted with Ox-/3-VLDL, oxidized low density lipoproteins, or polyinosinic acid (80-90%). The capacity of Kupffer cells to associate with and degrade l2S I-Ox-/3-VLDL appears to be twofold higher than for endothelial cells. It is concluded that on oxidation of /3-VLDL, the recognition system responsible for the uptake of fi-VLDL from the blood circulation is shifted from the remnant receptor to a specific oxidized-lipoprotein receptor. The efficiency of the scavenger activity on Kupffer cells will then form the protection system against the prolonged circulation of these atherogenic lipoproteins in the blood. (Arteriosclerosis and Thrombosis 1992;12:41-49) A accelerated rate of the vascular deposition of lipids is observed in patients suffering from type II or type III hyperlipoproteinemia.

P-Migrating very-low-density lipoproteins (P-VLDL) are cholesteryl-ester-enriched lipoproteins which accumulate in the serum of cholesterol-fed animals or patients with type 111 hyperlipoproteinemia. In the rat, P-VLDL are rapidly cleared by the liver and parenchymal liver cells form the major site for uptake. In this investigation, P-VLDL were labeled with [3H]cholesteryl esters and the hepatic intracellular transport of these esters was followed. 2 min after injection, the major part of the [3H]cholesteryl esters is already associated with the liver and a significant proportion is recovered in endosomes. Up to 25 rnin after injection, an increase in radioactivity in the lysosomal compartment is noticed. This radioactivity initially represents cholesteryl esters, while from 25 min onward, radioactivity is mainly present in unesterified cholesterol. Between 45 rnin and 90 min after P-VLDL injection, specific transfer of unesterified [3H]cholesterol to the endoplasmic reticulum is observed, while by 3 h the majority is located in this fraction. The appearance of radioactivity in the bile was rather slow as compared to the rapid initial uptake and processing, and up to 5 h after injection only 10% of the injected dose had reached the bile (mainly as bile acids). 72 h after injection, the amount of the injected radioactivity recovered in the bile had increased to 50%. Chloroquine treatment of the rats inhibited the hydrolysis of the cholesteryl esters and the appearance of radioactivity in the bile was retarded.It is concluded that P-VLDL are rapidly processed by parenchymal liver cells and that the cholesteryl esters from P-VLDL are hydrolyzed in the lysosomal compartment. Unesterified cholesterol remains associated with the endoplasmic reticulum for a prolonged time, although ultimately the majority will be secreted into the bile as bile acids. The effective operation of this pathway will prevent extrahepatic accumulation of cholesteryl esters from P-VLDL, while the prolonged residence time of unesterified cholesterol in the endoplasmic reticulum might be important for regulation of low-density lipoprotein (LDL) receptors in liver and thus for LDL levels in the blood.An abnormal form of very-low-density lipoproteins (VLDL) can be recognized in laboratory animals fed a diet high in fat and cholesterol, and in humans with the genetic disorder type I11 hypercholesterolemia [l -41. In comparison to normal VLDL, the so-called j-VLDL are enriched in cholesteryl esters and on electrophoresis it show p mobility [5].The presence of P-VLDL in the blood is associated with an increased risk of atherosclerosis [6] and in vitro this lipoprotein can provoke intracellular cholesterol(ester) accumulation in monocytes and macrophages whereby these cells are converted to foam cells which have a similar appearance to cells found in the atherosclerotic plaque [3, 7-91, In cholesterolfed animals, P-VLDL accumulation may be induced by a saturation of the hepatic clearance system [lo] or as consequence of an increased synthesis of the p...

No abstract