Turnover and tissue sites of degradation of glucosylated low density lipoprotein in normal and immunized rabbits.
Immunological mechanisms have been implicated in the atherogenic process since immunoglobulins are frequently found in the atherosclerotic aorta. We have previously shown that modifications of homologous low density lipoproteins (LDL) make it immunogenic. In particular we have demonstrated that immunization with homologous nonenzymatically glucosylated LDL (glcLDL) results in the generation of antibodies specific to the derivatized lysine residue, and that such antibodies do not react with native LDL epitopes. In the present study we immunized rabbits with reductively glucosylated rabbit LDL and then determined the effects of the circulating antibodies on the rates of plasma clearance and on the sites of degradation of LDL in which varying degrees of glucosylation had been achieved. In normal chow-fed animals, the plasma clearance of glcLDL was retarded in proportion to the extent of lysine derivatization. In contrast, in immunized animals the clearance of glcLDL was greatly accelerated. When 10% or more of lysine residues were derivatized, clearance of glcLDL was accelerated 50- to 100-fold. Even when only 5% of lysines were derivatized, plasma clearance was accelerated 2- to 3-fold. Cholesterol feeding inhibited LDL clearance from plasma and decreased LDL uptake of LDL receptor-rich tissues. In a similar manner, glucosylation of LDL inhibited its ability to bind to the LDL receptor and redirected sites of LDL degradation away from LDL receptor-rich tissues. Thus degradation of glcLDL by liver and adrenal was markedly diminished. The presence of antibodies to glcLDL also redirected sites of degradation of the modified LDL, primarily to the reticuloendothelial cells of the liver. There was no evidence for specific targeting of glcLDL-immunoglobulin complexes to the aorta; instead they were targeted to the liver. These data suggest that the presence of humoral antibodies to modified LDL acts to rapidly remove such LDL from plasma and specifically targets such complexes to reticuloendothelial cells, primarily in the liver. In this manner such antibodies may serve a useful purpose.
Wiklund
O
O
Department of Medicine, University of California, San Diego, La Jolla 92093.
Witztum
J L
JL
Carew
T E
TE
Pittman
R C
RC
Elam
R L
RL
Steinberg
D
D
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001323:Autoantibodies / Q000032:analysis*; D001665:Binding Sites; D002791:Cholesterol, Dietary / Q000378:metabolism; D017127:Glycation End Products, Advanced; D007114:Immunization; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D011817:Rabbits; D013154:Spleen / Q000378:metabolism; D000093844:Glycated Proteins
D001323:Autoantibodies; D002791:Cholesterol, Dietary; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins