Glucosylceramide Metabolism in Cultured Skin Fibroblasts

Glucosylceramide (Glc-cer) consists of equimolar portions of the long-chain amino alcohol, that is, sphingosine, a long-chain fatty acid, and glucose. Gaucher disease is caused by a genetically determined defect in the degradation of Glc-cer by Glc-cer β-glucosidase which results in an accmulation of Glc-cer in certain organs. Glc-cer is derived from the degradation of ganglioside in the brain and viscera, lactosylceramide in white blood cells, and glycosphingolipids and globotetraosylceramide in red blood cells. Gaucher disease is classified into three major clinical types. All three types have a deficiency of Glc-cer β-glucosidase. The residual activity measured in vitro does not reflect the severity of the disease. β-Glucosidase activity has been assayed exclusively in vitro. It recently has become apparent that mesurement of lysosomal enzyme in vivo provides new information regarding lipid metabolism. In this study the uptake and subseqent metabolism of (14C) stearic acid-labelled Glc-cer into cultured skin fibroblasts from controls, patients with type I and type II Gaucher disease were examined. There was no significant differences in the uptake of Glc-cer between the cultured cells from controls and from patients with Gaucher disease. In each cell line, Glc-cer was metabolized to ceramide and fatty acid, which was reutilized in the synthesis of major lipids found in the cultured fibroblasts. But the rate of hydrolysis in Gic-cer taken up by the cells was different in each of the type. Cells from the controls could metabolize 80% of the Glc-cer after 6 days. While, cells from type II and type I Gaucher disease could metabolize 50% and 60%, respectively. These results are in contrast to the in vitro results which demonstrated a very low activity for β-glucosidase in each type of Gaucher disease, and reflect the severity of the clinical course of this disease