title: 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.
abstract: 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)
authors.affiliation: Atlantic Research Centre, Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
authors.forename: H S
authors.initials: HS
authors.lastname: Sidhu
authors.forename: S A
authors.initials: SA
authors.lastname: Rastogi
authors.forename: D M
authors.initials: DM
authors.lastname: Byers
authors.forename: D L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: H W
authors.initials: HW
authors.lastname: Cook
authors.forename: F B
authors.initials: FB
authors.lastname: Palmer
authors.forename: M W
authors.initials: MW
authors.lastname: Spence
mesh_terms: D001769:Blood; D015152:Blotting, Northern; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D004951:Esterification; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
chemical_list: D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase