The glycosphingolipids (GSL) and other major lipid classes are studied in cultured fibroblasts from a family with familial hypercholesterolemia. The GSL content in cells grown in medium containing fetal calf serum was increased 5 fold in the homozygote and 2 to 3 fold in both heterozygous parents. Cell surface labeling experiments, using the membrane probe galactose oxidase followed by reduction with KB3H4, showed an increased incorporation of 3H by the homozygous cells into GL4 (4 fold), GM3 (2 to 3 fold), and GL3a and GD3 (1 to 2 fold); the amount of 3H incorporated by the heterozygous cells was in between that of the homozygous and normal fibroblasts. The specific radioactivity of each of the GSL, except GL2a, was lower in the mutant cells. This unlabeled pool of GSL may be buried in the membrane matrix (less exposure), or located intracellularly, or both. The phospholipids were most markedly elevated (3 fold) in homozygous cells, with a disproportionate increase in phosphatidic acid and sphingomyelin (5 to 6 fold). The content of the GSL, except GL2a, and of the phospholipids was reduced about one half in the homozygous fibroblasts grown in lipoprotein deficient medium for 24 hr; by 5 days the GSL content was reduced to only 1.3 times normal and phospholipids to below normal. Incubation of normal fibroblasts in lipoprotein deficient medium 24 hr had no effect on the GSL or phospholipid content; at 5 days, there was a 50% increase in both GL3a and GL4 with a 25% increase in GM3; there was no change in the phospholipid content. These data suggest that the defective regulation of lipid metabolism in this syndrome may be more extensive than previously realized.
|Original language||English (US)|
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 1976|
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