title: Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.
abstract: The binding of 125I-lipoprotein (a) [Lp(a)] to cell surface receptors was studied on cultured human fibroblasts. The results were compared with corresponding data obtained with 125I-low density lipoproteins (LDL). Equilibrium binding studies showed that Lp(a) is bound with high affinity by the cell surface receptors. The maximum binding capacity for Lp(a) was 37% lower than for LDL. For Lp(a) and LDL, the Scatchard plots displayed linearity, indicating a single category of binding sites. Half-maximal saturation occurred at a concentration of 9.52 +/- 1.04 nM for Lp(a) and 7.76 +/- 1.29 nM for LDL. Competition binding experiments revealed that Lp(a) and LDL are nearly equally potent in competing each other for the binding sites. Binding of Lp(a) and LDL were followed by suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cyclohexanedione treatment of Lp(a) and LDL completely abolished receptor binding. Neither Lp(a) nor LDL were specifically bound by fibroblasts obtained from a patient with homozygous familial hypercholesterolemia (FH). The removal mechanisms for Lp(a) and LDL were further compared by in vivo studies. Radioiodinated Lp(a) and LDL were injected intravenously into 12 normolipemic individuals to measure kinetic parameters of these two lipoproteins simultaneously in each subject. Mean fractional catabolic rate (FCR) of Lp(a) was 0.260 +/- 0.060 and mean FCR of LDL was 0.377 +/- 0.077 (mean +/- SD). In each subject, FCR of Lp(a) was lower than the FCR of LDL; the mean difference was 31%. The absolute synthetic rate of Lp(a) was significantly lower than the corresponding value of LDL. In each individual, the percentage of total Lp(a) that was contained in the intravascular space was higher than the corresponding value of LDL; the mean difference was 19%. A highly significant positive correlation was found between FCR of LDL and FCR of Lp(a) (r = 0.853, P less than 0.01). No relationship was found between the serum concentration of LDL-apolipoprotein B and Lp(a). The serum level of Lp(a) was positively related to the absolute rate of Lp(a) synthesis (r = 0.979, P less than 0.01). The serum level of LDL-apolipoprotein B was inversely related to FCR of LDL (r = 0.613, P less than 0.05). In a patient with homozygous FH, FCR of LDL was 0.205 and FCR of Lp(a) was 0.210. The results of these studies show that Lp(a) is specifically bound with high affinity to the same receptors of human fibroblasts as LDL. The affinity and maximum binding capacity are slightly lower for Lp(a) than for LDL. The results of the turnover studies are consistent with the assumption that Lp(a) is removed from the plasma by similar mechanisms as LDL.
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001667:Binding, Competitive; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism; D007700:Kinetics; D017270:Lipoprotein(a); D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018110:Receptors, Lipoprotein
chemical_list: D003512:Cyclohexanones; D017270:Lipoprotein(a); D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; C018031:1,2-cyclohexanedione; D006903:Hydroxymethylglutaryl CoA Reductases