Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells

T J Van Berkel,Y B De Rijke,J K Kruijt

doi:10.1016/s0021-9258(18)52241-9

Abstract

Human low density lipoprotein was oxidized (Ox-LDL) by exposure to 5 microM Cu2+ and its fate in vivo was compared to acetylated low density lipoprotein (Ac-LDL). Ox-LDL, when injected into rats, is rapidly removed from the blood circulation by the liver, similarly as Ac-LDL. A separation of rat liver cells into parenchymal, endothelial, and Kupffer cells at 10 min after injection of Ox-LDL or Ac-LDL indicated that the Kupffer cell uptake of Ox-LDL is 6.8-fold higher than for Ac-LDL, leading to Kupffer cells as the main liver site for Ox-LDL uptake. In vitro studies with isolated liver cells indicated that saturable high affinity sites for Ox-LDL were present on both endothelial and Kupffer cells, whereby the capacity of Kupffer cells to degrade Ox-LDL is 6-fold higher than for endothelial cells. Competition studies showed that unlabeled Ox-LDL competed as efficiently (90%) as unlabeled Ac-LDL with the cell association and degradation of 125I-labeled Ac-LDL by endothelial and Kupffer cells. However, unlabeled Ac-LDL competed only partially (20-30%) with the cell association and degradation of 125I-labeled Ox-LDL by Kupffer cells, while unlabeled Ox-LDL or polyinosinic acid competed for 70-80%. It is concluded that the liver contains, in addition to the scavenger (Ac-LDL) receptor which interacts efficiently with both Ac-LDL and Ox-LDL and which is concentrated on endothelial cells, an additional specific Ox-LDL receptor which is highly concentrated on Kupffer cells. In vivo the specific Ox-LDL recognition site on Kupffer cells will form the major protection system against the occurrence of the atherogenic Ox-LDL particles in the blood.

Highlights

Different Fate in Vivo of Oxidatively Modified Low Density Lipoprotein andAcetylated Low Density Lipoprotein in Rats
It is suggested that mouse peritoneal macrophages have at least two classes of scavenger receptors: 1) an acetylated LDL (Ac-LDL) receptor which recognizes both Ac-LDL and OxLDL with similar affinities; 2) an Ox-LDL receptor which recognizes Ox-LDL but not Ac-LDL
Obtainedwith three different liver cell types indicate that in the liver various scavenger receptors are responsible for the interaction of Ox-LDL with the liver

Summary

RESULTS

The kinetics of the initial liver association of 6 or 20 h Ox-LDL are similar to that of acetylated LDL (Ac-LDL) (Fig. 2) It appears that thedecline in liver-associated radioactivity of Ac-LDL, due to lysosomal degradation of the apolipoproteins [9], proceeds more rapidly than with Ox-LDL. Both the liver association of Ox-LDL (20 h) andAc-LDL are inhibited by preinjection (1min prior to Ac-LDL or Ox-LDL) of polyinosinic acid (Fig. 2). Cellular Distribution of Ox-LDL and Ac-LDL in Liver-We have shown previously that within the liver Ac-LDL is mainly taken up by endothelial cells In agreement with these data the highest specificuptake (permg ofcell protein) of Ac-LDL at 10 min after injection is found to be associated with endothelial cells (Fig. 3). The livers were not perfused and the dotted line represents the maximal contribution of the serum value to the liveruptake(determined with "-labeled albumin)

TABLE I

Parenchymal cells

Endotheliacl ells

DISCUSSION