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 demon- strated that immunization with homologous nonenzymatically glucosylated LDL (glcLDL) results in the generation of anti- bodies specific to the derivatized lysine residue, and that such anti- bodies do not react with native LDL epitopes. In the present study we immunized rabbits with reductively glucosylated rab- bit LDL and then determined the effects of the circulating anti- bodies 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 Sfold. 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 an- tibodies 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-im- munoglobulin complexes to the aorta; instead they were targeted to the 1iver.M 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 retic- uloendothelial cells, primarily in the liver. In this manner such antibodies may serve a useful purpose.- Wiklund, O., J. L. Witztum, T. E. Cam, R. C. Pittman, R. L. Elam, and D. Steinberg. Turnover and tissue sites of degradation of gluco- sylated low density lipoprotein in normal and immunized rab- bits. J Lipid Res. 1987. 28: 1098 - 1109. Plasma low density lipoproteins (LDL) are a major source for the cholesterol deposited in the arterial wall during the development of atherosclerosis. Abnormalities in the metabolism of LDL and shifts in its sites of degradation therefore may be of great importance for the development of atherosclerotic lesions. Immunological mechanisms that modify LDL catabolism have been dis- cussed by several investigators. In so-called "autoimmune hyperlipidemia" or in association with paraproteinemia, autoantibodies against LDL have been demonstrated