Receptor-mediated catabolism of low density lipoprotein in man. Quantitation using glucosylated low density lipoprotein.
Low density lipoprotein (LDL) catabolism occurs by LDL receptor-dependent and LDL receptor-independent pathways. We have shown previously that nonenzymatic glucosylation of LDL in the presence of cyanoborohydride irreversibly blocks the lysine residues of LDL. Glucosylated LDL (GLC-LDL) was not degraded by the LDL receptor of fibroblasts, and its degradation by macrophages was similar to that of native LDL. This suggested that GLC-LDL should be a good tracer of LDL receptor-independent catabolism, and if combined with a tracer of total LDL catabolism, should enable one to calculate the extent of LDL receptor-dependent catabolism. To determine the contribution of each pathway in man, we prepared (125)I-GLC-LDL and (131)I-control LDL and simultaneously determined the fractional catabolic rate (FCR) of each tracer in four subjects. In preliminary experiments, we showed that the conditions for glucosylation did not affect LDL turnover. In the four subjects, the FCR for total LDL catabolism ranged from 0.345 to 0.724 d(-1) with a mean of 0.57+/-0.16 d(-1). The FCR of GLC-LDL varied from 0.071 to 0.141 d(-1) with a mean of 0.11+/-0.03 d(-1). The latter is similar to the FCR reported for native LDL in subjects with homozygous familial hypercholesterolemia, supporting the interpretation that GLC-LDL traces only the receptor-independent pathway. Despite the wide range of total LDL catabolism in these subjects. LDL receptor-independent catabolism accounted for only 19.5-20.6% of total catabolism. In turn, LDL receptor-dependent catabolism accounted for 80% of total clearance in each person. Furthermore, while the decay curve of LDL showed the usual biphasic pattern, the decay curve of GLC-LDL was monoexponential in each subject even when followed for as long as 48 d. This suggests that LDL receptor activity is responsible for the biphasic nature of LDL decay. These studies emphasize the central role of LDL receptor activity in normal LDL metabolism in man.
D000328:Adult; D001894:Borohydrides / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000032:analysis*; D011973:Receptors, LDL; D013997:Time Factors
D001894:Borohydrides; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D005947:Glucose