Regulation of low density lipoprotein receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase activities are differentially affected in Niemann-Pick type C and type D fibroblasts.

Defective regulation of intracellular cholesterol metabolism has been investigated in cultured fibroblasts from two subtypes of Niemann-Pick type II disease: the panethnic Niemann-Pick type C (NPC) and the Nova Scotia type D (NPD). Cell extracts from NPC and NPD fibroblasts cultured in lipoprotein-deficient medium exhibited activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase that were two-fold greater than in normal cells. Addition of serum resulted in only a 15% decrease in HMG-CoA reductase activity within 6 h in these cells, compared with a decrease of 80% in normal fibroblasts. The initial rate of return to maximal values for the first 6 h after removal of serum was similar in all three cell types; thereafter, the rate was faster in the mutant fibroblasts. Binding and internalization of 125I-labeled low density lipoprotein (LDL) was not decreased within 12 h of incubation of NPC fibroblasts with serum, while a decrease of 50% was observed for both NPD and normal fibroblasts over this time period. Northern blot analysis also indicated a slower decrease in steady-state LDL receptor mRNA in NPC relative to normal and NPD cells. In all three cell types, inhibition of HMG-CoA reductase with mevinolin had no effect on serum-stimulated cholesterol esterification, while inhibition of acyl-CoA:cholesterol acyltransferase with Sandoz 58-035 did not influence HMG-CoA reductase activity, indicating that defects in these regulatory mechanisms are independent.(ABSTRACT TRUNCATED AT 250 WORDS)