Uptake and catabolism of modified LDL in scavenger-receptor class A type I/II knock-out mice

The liver is the major organ responsible for the uptake of modified low-density lipoprotein (LDL) from the blood circulation, with endothelial and Kupffer cells as major cellular uptake sites. Scavenger-receptors, which include various classes; are held responsible for this uptake. Mice deficient in scavenger-receptor class A types I and II were created and the fate of acetylated LDL (Ac-LDL) in vivo and its interaction with liver endothelial, Kupffer and peritoneal macrophages was characterized. Surprisingly, the decay in vivo (t(1/2) < 2 min), tissue distribution and liver uptake (at 5 min it was 77.4+/-4.6% of the injected dose) of Ac-LDL in the knock-out mice were not significantly different from control mice (t < 2 min and liver uptake 79.1+/-4.6% of the injected dose). A separation of mice liver cells into parenchymal, endothelial and Kupffer cells 10 min after injection of Ac-LDL indicated that in both control and knock-out mice the liver endothelial cells were responsible for more than 70% of the liver uptake. Both in control and knockout mice: preinjection of polyinosinic acid (poly I, 200 mu g) completely blocked the liver uptake, indicating that both in control and knock-out mice the scavenger-receptors are sensitive to poly I, Preinjection of suboptimal poly I concentrations (20 and 50 mu g) provided evidence that the serum decay and liver uptake of Ac-LDL is more readily inhibited in the knock-out mice as compared with the control mice, indicating less efficient removal of Ac-LDL in vivo in the knock-out mice under these conditions. Studies in vitro with isolated liver endothelial and Kupffer cells from knock-out mice indicate that the cell association of Ac-LDL during 2 h at 37 degrees C is 50 and 53% of the control, respectively, whereas the degradation reaches values of 58 and 63%. For peritoneal macrophages from knock-out mice the cell association of Ac-LDL was identical to the control mice whereas the Ac-LDL degradation in cells from the knock-out mice was 17%, of the control. The low degradation capacity of peritoneal macrophages from knock-out mice for Ac-LDL indicates that scavenger-receptor class A types I and II play a quantitative important role in the degradation of Ac-LDL by macrophapes. In liver, the contribution of scavenger-receptor class A types I and II to the maximal uptake and degradation of Ac-LDL by endothelial and Kupffer cells was 40-50%. Binding studies performed at 4 degrees C indicate that the lower rates of degradation are due to a lower number of surface receptors on the cells from the knock-out mice. From the in vitro and in vivo data it can be concluded that in addition to the classic scavenger-receptors class A types I and II liver does contain additional novel poly I-sensitive scavenger-receptors that facilitate efficient removal of Ac-LDL from the blood circulation. The availability of the scavenger-receptor class A types I and II knock-out mice will stimulate further molecular identification of these receptors.