Increase in glycosaminoglycan synthesis in familial hypercholesterolemic fibroblasts.
The enzymes of biosynthesis are usually bound to membranes and require an undisturbed lipid environment for regulated activity. In familial hypercholesterolemia, this lipid environment is disturbed and there is a low cholesterol ester level in the cellular membranes that results from impaired processing of low density lipoprotein (LDL). Thus, altered activities of various synthesizing enzymes could be expected. In this study, we found that microsomal glucuronyltransferase activity was 3.4-fold higher in homozygous familial hypercholesterolemic skin fibroblasts (n = 5) than in normal fibroblasts (n = 8). The secretion rates of glycosaminoglycans in familial hypercholesterolemia were also higher and the incorporation of radiolabeled precursor into glycosaminoglycans was enhanced. In addition to the differences in total synthesis and secretion, we found an altered pattern of individual glycosaminoglycan species with respect to the carbohydrate backbone and a different degree of sulfation in familial hypercholesterolemia. Heparan sulfate with a high degree of sulfation was secreted at a particularly high rate by hypercholesterolemic fibroblasts. Although the affinity of this glycosaminoglycan for LDL is lower than that of dermatan sulfate, it might cause formation of enhanced LDL-glycosaminoglycan complex and induce the xanthomas and atheromas of familial hypercholesterolemia.
D005347:Fibroblasts / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism* / Q000473:pathology
D006025:Glycosaminoglycans; D014453:Glucuronosyltransferase