Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.
Monolayers of cultured fibroblasts from normal human subjects bind (125)I-labeled low-density lipoproteins with high affinity and specificity. High affinity binding of similar magnitude was not observed in cells from five unrelated subjects with the homozygous form of familial hypercholesterolemia. In normal cells incubated at 37 degrees , the binding sites were saturated at a low-density lipoprotein concentration of 20 mug/ml. A maximum of approximately 250,000 molecules could be bound to each cell. Whole serum and very-low-density lipoproteins displaced (125)I-labeled low-density lipoproteins from the binding sites, but high-density lipoproteins, the lipoprotein-deficient fraction of serum, and abetalipoproteinemic serum did not. This binding appears to be a required step in the process by which low-density lipoproteins normally suppress the synthesis of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. The demonstration of a defect in binding of low-density lipoproteins to cells from subjects with the homozygous form of familial hypercholesterolemia appears to explain the previously reported failure of lipoproteins to suppress the synthesis of this enzyme and hence may account for the overproduction of cholesterol that occurs in these cultured cells.
D000328:Adult; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D005977:Glutarates; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D007231:Infant, Newborn; D007457:Iodine Radioisotopes; D007700:Kinetics; D008074:Lipoproteins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid
D005977:Glutarates; D007457:Iodine Radioisotopes; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000429:Alcohol Oxidoreductases; D008798:Mevalonic Acid