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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

Published on: June 3, 2016

Down-regulation of FoxO-dependent c-FLIP expression mediates TRAIL-induced apoptosis in activated hepatic stellate

Soo-Jung Park1, Hee-Young Sohn, Jeongsook Yoon

  • 1Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul 122-701, South Korea.

Cellular Signalling
|May 28, 2009
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in activated hepatic stellate cells by inhibiting PI3K/Akt signaling, leading to FoxO nuclear accumulation and reduced c-FLIP expression. This mechanism supports TRAIL as a potential antifibrotic therapy for liver fibrosis.

Area of Science:

  • Hepatology
  • Cell Biology
  • Molecular Biology

Background:

  • Activated hepatic stellate cells (HSCs) are key drivers of liver fibrosis.
  • Targeting activated HSCs is crucial for antifibrotic therapies.

Purpose of the Study:

  • To investigate the mechanism by which TRAIL induces apoptosis in activated human HSCs (LX-2 cells).
  • To explore the role of the PI3K/Akt/FoxO signaling pathway in TRAIL-mediated apoptosis of LX-2 cells.

Main Methods:

  • Treatment of LX-2 cells with TRAIL.
  • Analysis of FoxO protein localization and phosphorylation.
  • Assessment of apoptosis-related signaling molecules (caspase-8, -3, Bid, cytochrome c).
  • siRNA-mediated knockdown of FoxO and c-FLIP expression analysis.
  • Transfection of LX-2 cells with c-FLIP.

Main Results:

  • TRAIL inhibited PI3K/Akt-dependent FoxO phosphorylation, promoting FoxO nuclear translocation in LX-2 cells.
  • Nuclear FoxO accumulation led to decreased c-FLIP(L/S) expression.
  • This resulted in activation of apoptosis pathways (caspase-8, -3, Bid) and cytochrome c release.
  • FoxO knockdown or c-FLIP overexpression conferred resistance to TRAIL-induced apoptosis.

Conclusions:

  • TRAIL-induced apoptosis in LX-2 cells is mediated by PI3K/Akt suppression, FoxO activation, and subsequent c-FLIP downregulation.
  • This pathway highlights TRAIL as a promising therapeutic strategy for liver fibrosis.

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