Contribution of the receptor pathway to low density lipoprotein catabolism in humans. New methods for quantitation

Receptor-mediated catabolism of low density lipoprotein (LDL) by cultured cells depends on the presence of functionally significant arginine and lysine residues on the lipoprotein apoprotein. When these are blocked, the recognition process is abolished, and catabolism of the modified lipoprotein is restricted to other mechanisms. Accurate discrimination between the activities of the receptor and nonreceptor pathways in vivo depends critically on the metabolic properties of this chemically modified lipoprotein. Here we report our experiences with two lysine-modified LDL tracers, glucosylated LDL (GLC-LDL) and 2-hydroxyacetaldehyde-treated LDL (HOET-LDL). The fractional clearance rate of GLC-LDL (0.25 +/- 0.05 pools/day, n = 5) was 50% of that of control material (0.51 +/- 0.09 pools/day) injected simultaneously into normal subjects. The HOET-LDL was also retarded in its clearance. Here, however, the fractional clearances of the control (0.37 +/- 0.06 pools/day, n = 6) and modified lipoprotein (0.19 +/- 0.03 pools/day) were lower than those obtained by the glucosylation procedure. We suspect that the prolonged incubation required for glucosylation of LDL artifactually accelerated its catabolism. The HOET-LDL does not suffer from this defect and seems to be a better tracer of the receptor-independent pathway. In a group of 10 subjects, HOET-LDL was metabolically indistinguishable from 1,2 cyclohexanedione-treated, arginine-modified LDL.