Altered sensitivities to potential inhibitors of cholesterol biosynthesis in Niemann-Pick type C fibroblasts

Cell Struct Funct. 1993 Aug;18(4):231-40. doi: 10.1247/csf.18.231.


Cultured fibroblasts from patients with Niemann-Pick disease type C (NP-C) are characterized by the lysosomal accumulation of unesterified cholesterol and the inability of low-density lipoprotein (LDL) to stimulate cholesterol esterification, in addition to impaired LDL-mediated down-regulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in the transport of cholesterol from lysosomes to other intracellular membrane sites has been suggested, it is unclear how cells regulate the levels of cellular sterols and whether their membrane cholesterol requirements are satisfied or not. We studied the esterification of exogenously added cholesterol, total levels of cellular cholesterol and cholesteryl ester, cholesterol synthesis from a two-carbon precursor, and sensitivities to potential inhibitors of cholesterol biosynthesis in proliferating NP-C cells. We observed the following: (a) esterification of [3H]cholesterol was decreased but the total amount of cellular cholesteryl ester was not decreased; (b) synthesis of cholesterol from [3H]acetate was increased; and (c) cells were hypersensitive to cholecalciferol, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, and were resistant to filipin, which binds to membrane sterols and presumably damages the membrane. The results indicate that NP-C cells depend on the cellular cholesterol synthetic pathway for their proliferation, but the plasma membrane sterols are presumably decreased. The altered sensitivities to potential inhibitors of cholesterol biosynthesis should be a useful marker for diagnosis and genetic studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / metabolism
  • Adult
  • Amphotericin B / pharmacology
  • Anticholesteremic Agents / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerulenin / pharmacology
  • Child
  • Cholecalciferol / pharmacology
  • Cholesterol / biosynthesis*
  • Cholesterol Esters / biosynthesis*
  • Fibroblasts / metabolism
  • Filipin / pharmacology
  • Humans
  • Japan
  • Lipids / analysis
  • Male
  • Niemann-Pick Diseases / metabolism*
  • Niemann-Pick Diseases / pathology
  • Pravastatin / pharmacology


  • Acetates
  • Anticholesteremic Agents
  • Cholesterol Esters
  • Lipids
  • Cerulenin
  • Cholecalciferol
  • Amphotericin B
  • Filipin
  • Cholesterol
  • Pravastatin