Cholesterol movement in Niemann-Pick type C cells and in cells treated with amphiphiles

J Biol Chem. 2000 Jun 9;275(23):17468-75. doi: 10.1074/jbc.M000875200.


Cholesterol accumulates to massive levels in cells from Niemann-Pick type C (NP-C) patients and in cells treated with class 2 amphiphiles that mimic NP-C disease. This behavior has been attributed to the failure of cholesterol released from ingested low density lipoproteins to exit the lysosomes. However, we now show that the rate of movement of cholesterol from lysosomes to plasma membranes in NP-C cells is at least as great as normal, as was also found previously for amphiphile-treated cells. Furthermore, the lysosomes in these cells filled with plasma membrane cholesterol in the absence of lipoproteins. In addition, we showed that the size of the endoplasmic reticulum cholesterol pool and the set point of the homeostatic sensor of cell cholesterol were approximately normal in NP-C cells. The plasma membrane cholesterol pools in both NP-C and amphiphile-treated cells were also normal. Furthermore, the build up of cholesterol in NP-C lysosomes was not a physiological response to cholesterol overload. Rather, it appeared that the accumulation in NP-C lysosomes results from an imbalance in the brisk flow of cholesterol among membrane compartments. In related experiments, we found that NP-C cells did not respond to class 2 amphiphiles (e.g. trifluoperazine, imipramine, and U18666A); these agents may therefore act directly on the NPC1 protein or on its pathway. Finally, we showed that the lysosomal cholesterol pool in NP-C cells was substantially and preferentially reduced by incubating cells with the oxysterols, 25-hydroxycholesterol and 7-ketocholesterol; these findings suggest a new pharmacological approach to the treatment of NP-C disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstenes / pharmacology*
  • Anticholesteremic Agents / pharmacology
  • Cell Line
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Culture Media
  • Endoplasmic Reticulum / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Homeostasis
  • Humans
  • Imipramine / pharmacology*
  • Kinetics
  • Lipoproteins / physiology
  • Lysosomes / metabolism
  • Membrane Lipids / metabolism
  • Monensin / pharmacology
  • Niemann-Pick Diseases / metabolism*
  • Niemann-Pick Diseases / pathology
  • Skin / metabolism*
  • Trifluoperazine / pharmacology*


  • Androstenes
  • Anticholesteremic Agents
  • Culture Media
  • Lipoproteins
  • Membrane Lipids
  • Trifluoperazine
  • 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
  • Monensin
  • Cholesterol
  • Imipramine