Impaired hepatocyte binding, uptake and degradation of glucosylated low-density lipoproteins

The catabolism of low-density lipoproteins (LDL), the major cholesterol-carrying lipoproteins in plasma, is mediated in part via a high-affinity uptake pathway in the liver. Non-enzymatic glucosylation of lysine residues of apolipoprotein B, the major protein of LDL, blocks receptor-mediated uptake of LDL by fibroblasts and endothelial cells. We investigated the effect of the degree of glucosylation on the binding, uptake and degradation of radioiodinated LDL by the human hepatoma cell line Hep G2. Human LDL was glucosylated with 250 mM glucose and 30 mM cyanoborohydride at 37 degrees C. Incubations ranging from 3 to 48 h in duration resulted in the formation of 6-27% of glucitol-lysine adducts as demonstrated by coincubation with [14C]glucose. The degree of glucose incorporation corresponded to the extent of inhibition of binding, uptake and degradation of LDL (10-90%). The data are consistent with the view that glucosylation of LDL markedly impairs their catabolism. This phenomenon may be related to the pathophysiology of the premature atherosclerosis observed in diabetes mellitus.