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 cultu red in lipoprotein-deficient medium exhibited activities of 3-hydroxy- 3-methylglutaryl-CoA (HMG-CoA) reductase that were two-fold greater th an 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 t o 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 I-125-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 analys is also indicated a slower decrease in steady-state LDL receptor mRNA in NPC relative to normal and NPD cells. In all three cell types, inhi bition of HMG-CoA reductase with mevinolin had no effect on serum-stim ulated cholesterol esterification, while inhibition of acyl-CoA:choles terol acyltransferase with Sandoz 58-035 did not influence HMG-CoA red uctase activity, indicating that defects in these regulatory mechanism s are independent. Together with previous observations that NPC and NP D fibroblasts exhibit different levels of cholesterol accumulation and esterification, our results suggest that NPD may result from a distin ct mutation in a Niemann-Pick type II gene, in which different mutatio ns can differentially alter the various mechanisms of cholesterol regu lation.