Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans.
The sulfated glycosaminoglycan, heparin, was found to release 125I-labeled low density lipoprotein (125I-LDL) from its receptor site on the surface of normal human fibroblasts. Measurement of the amount of 125I-LDL released by heparin permitted the resolution of the total cellular uptake of 125I-LDL at 37 degrees C into two components: first, an initial rapid, high affinity binding of the lipoprotein to the surface receptor, from which the 125I-LDL could be released by heparin, and second, a slower process attributable to an endocytosis of the receptor-bound lipoprotein, which rendered it resistant to heparin release. At 4 degrees C the amount of heparin-releasable 125I-LDL was similar to that at 37 degrees C, but interiorization of the lipoprotein did not occur at the lower temperature. The physiologic importance of the cell surface LDL receptor was emphasized by the finding that mutant fibroblasts from a subject with homozygous Familial Hypercholesterolemia, which lack the ability to take up 125I-LDL at 37 degrees C, did not show cell surface binding of 125I-LDL, as measured by heparin release, at either 4 degrees C or 37 degrees C. Although heparin released 125I-LDL from its binding site, it did not release 3H-concanavalin A from its surface receptor, and conversely, alpha-methyl-D-mannopyranoside, which released 3H-concanavalin A, did not release surface-bound 125I-LDL. When added to the culture medium simultaneously with LDL, heparin prevented the binding of LDL to its receptor and hence prevented the LDL-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. The uptake of LDL by fibroblasts is proposed as a model of receptor-mediated adsorptive endocytosis of macromolecules in human cells.
D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000494:pharmacology; D003208:Concanavalin A / Q000378:metabolism; D003871:Dermatan Sulfate / Q000494:pharmacology; D004705:Endocytosis; D006493:Heparin / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008766:Methylmannosides / Q000494:pharmacology; D011955:Receptors, Drug; D013696:Temperature
D008077:Lipoproteins, LDL; D008766:Methylmannosides; D011955:Receptors, Drug; D003208:Concanavalin A; D003871:Dermatan Sulfate; D006493:Heparin; D002809:Chondroitin Sulfates