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Updated: Jun 16, 2026
10:12
Enrichment of Mammalian Tissues and Xenopus Oocytes with Cholesterol
Published on: March 25, 2020
Cholesterol trafficking is required for mTOR activation in endothelial cells
Jing Xu1, Yongjun Dang, Yunzhao R Ren
1Department of Pharmacology and Oncology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Summary
Cholesterol levels impact cell growth signaling. Blocking cholesterol transport to lysosomes inhibits mammalian target of rapamycin (mTOR) in endothelial cells, revealing a new pathway for anti-angiogenesis drug discovery.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation.
- The influence of cholesterol homeostasis on mTOR signaling remains largely unexplored.
Purpose of the Study:
- To investigate the effect of cholesterol homeostasis on mTOR activity in endothelial cells.
- To explore the potential of targeting cholesterol trafficking pathways for anti-angiogenesis therapies.
Main Methods:
- Utilized itraconazole to block lysosomal cholesterol trafficking.
- Assessed mTOR activity inhibition and restoration via extracellular cholesterol.
- Employed siRNA knockdown of Niemann-Pick disease type C (NPC) 1 and NPC2.
- Investigated the effects of thapsigargin on cholesterol accumulation and mTOR inhibition.
Main Results:
- Blockade of lysosomal cholesterol trafficking by itraconazole inhibited mTOR activity in endothelial cells.
- mTOR inhibition by itraconazole was partially reversible with extracellular cholesterol.
- Inhibitors of endosomal/lysosomal cholesterol transport and NPC1/NPC2 knockdown also reduced mTOR activity.
- Thapsigargin reversed both lysosomal cholesterol accumulation and mTOR inhibition.
Conclusions:
- mTOR signaling in endothelial cells appears to sense membrane sterol concentrations.
- The cholesterol trafficking pathway represents a potential target for developing novel anti-angiogenesis agents.
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