Cholesterol pathways affected by small molecules that decrease sterol levels in Niemann-Pick type C mutant cells

PLoS One. 2010 Sep 21;5(9):e12788. doi: 10.1371/journal.pone.0012788.

Abstract

Background: Niemann-Pick type C (NPC) disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles.

Methodology/principal findings: The effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds.

Conclusions/significance: Results herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155-1165).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology*
  • CHO Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cholesterol / metabolism*
  • Cricetinae
  • Cricetulus
  • Drug Evaluation, Preclinical
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lipoproteins / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mutation*
  • Niemann-Pick Diseases / genetics
  • Niemann-Pick Diseases / metabolism*
  • Small Molecule Libraries / pharmacology*
  • Sterols / metabolism*

Substances

  • Anticholesteremic Agents
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipoproteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Small Molecule Libraries
  • Sterols
  • Cholesterol