Oxidized or acetylated low density lipoproteins are rapidly cleared by the liver in mice with disruption of the scavenger receptor class A type I/II gene.
Oxidized low density lipoprotein (LDL) and acetyl LDL are recognized by the scavenger receptor class A type I/II (SR-AI/II) on macrophages and liver endothelial cells. Several investigators have suggested that there are additional receptors specific for oxidized LDL, but characterization of these alternate receptors for oxidized LDL and evaluation of their quantitative importance in uptake of oxidized LDL has been difficult because of overlapping ligand specificity with SR-AI/II. The purpose of this study was to determine the importance of SR-AI/II in the removal of modified LDL from the bloodstream in vivo. The clearance rate of oxidized LDL from plasma in normal mice was very rapid, and > 90% of injected dose was removed from the blood within 5 min. Clearance rates of oxidized LDL were equally high in SR-AI/II knockout mice, indicating that this receptor is not required for removal of oxidized LDL from plasma. Surprisingly, there was no difference in the clearance rate of acetyl LDL in wild-type and SR-AI/II knockout animals. The plasma clearance of radioiodinated acetyl LDL was almost fully blocked by a 50-fold excess of unlabeled acetyl LDL, but the latter only inhibited oxidized LDL clearance by approximately 5%. Both modified LDLs were cleared mostly by the liver, and there was no difference in the tissue distribution of modified LDL in control and knockout mice. Studies in isolated nonparenchymal liver cells showed that Kupffer cells accounted for most of the uptake of oxidized LDL. Extensively oxidized LDL and LDL modified by exposure to fatty acid peroxidation products were efficient competitors for the uptake of labeled oxidized LDL by SR-AI/II-deficient Kupffer cells, while acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors.
Ling
W
W
Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
Lougheed
M
M
Suzuki
H
H
Buchan
A
A
Kodama
T
T
Steinbrecher
U P
UP
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D019327:Copper Sulfate / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008315:Malondialdehyde / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E
D001053:Apolipoproteins; D015815:Cell Adhesion Molecules; D008077:Lipoproteins, LDL; C495140:Msr1 protein, mouse; C495138:Olr1 protein, mouse; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D019327:Copper Sulfate