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. 1998 Apr 1;331(Pt 1):29–35. doi: 10.1042/bj3310029

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

T J Van Berkel 1, A Van Velzen 1, J K Kruijt 1, H Suzuki 1, T Kodama 1
PMCID: PMC1219317  PMID: 9512458

Abstract

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 (t12 < 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 (t12 < 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 knock-out mice, preinjection of polyinosinic acid (poly I, 200 microg) 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 microg) 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 macrophages. 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.

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Selected References

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