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Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R

Harilaos Filippakis1, Nicola Alesi1, Barbara Ogorek1

  • 1Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Oncotarget
|May 13, 2017
PubMed

Insights

Tuberous sclerosis complex (TSC) cells survive chloroquine treatment by upregulating cholesterol uptake. This pathway, dependent on TSC2, offers potential therapeutic targets for TSC.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder characterized by hyperactive mTORC1 signaling.
  • The role of TSC1/2 deficiency in lysosome-mediated cellular processes, particularly cholesterol homeostasis, remains unclear.

Purpose of the Study:

  • To investigate the impact of lysosomal inhibition on cholesterol metabolism in TSC2-deficient cells.
  • To elucidate the mechanisms underlying cell survival in TSC2-deficient cells under specific treatment conditions.

Main Methods:

  • Utilized chloroquine (CQ) to inhibit lysosomal function in TSC2-deficient and TSC2-expressing cells.
  • Analyzed gene expression related to cholesterol homeostasis.
  • Quantified intracellular cholesterol and cholesterol ester levels.
  • Investigated the role of LDL-R and Vps34 in endosomal trafficking and cholesterol uptake.

Main Results:

  • Chloroquine treatment upregulated cholesterol homeostasis genes in TSC2-deficient cells, leading to increased cholesterol and ester accumulation.
  • Combined inhibition of lysosomal function and de novo cholesterol synthesis promoted survival specifically in TSC2-deficient cells.
  • Cell survival was dependent on LDL-R-mediated exogenous cholesterol uptake and Vps34-dependent endosomal trafficking.
  • Inhibition of both lysosomal and endosomal trafficking impaired cholesterol uptake and cell growth in TSC2-deficient cells.

Conclusions:

  • TSC2 deficiency alters lysosome-mediated regulation of cholesterol homeostasis.
  • Targeting cholesterol uptake and trafficking pathways presents a potential therapeutic strategy for Tuberous Sclerosis Complex.
Keywords:
TSCchloroquinecholesterollysosomemTORC1

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