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Akt protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NK-kappa B activation

E Hatano1, D A Brenner

  • 1Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|November 14, 2001
PubMed

Insights

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects hepatocytes from Fas-mediated apoptosis by activating nuclear factor-kappa B (NF-kappa B), partly via Bcl-xL induction. This pathway is crucial for hepatocyte survival signaling.

Area of Science:

  • Cellular and Molecular Biology
  • Hepatology
  • Apoptosis Research

Background:

  • Hepatocyte apoptosis is implicated in liver diseases.
  • Tumor necrosis factor-alpha (TNF-alpha) and Fas receptor signaling can trigger apoptosis in hepatocytes.
  • The roles of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappa B) pathways in this process require elucidation.

Purpose of the Study:

  • To investigate the involvement of the PI3K/Akt and NF-kappa B pathways in protecting hepatocytes against TNF-alpha- and Fas-mediated apoptosis.
  • To delineate the signaling mechanisms by which these pathways confer protection.

Main Methods:

  • Primary mouse hepatocytes were pretreated with PI3K/Akt and NF-kappa B pathway inhibitors (pharmacological and adenovirus-mediated).
  • Cells were subsequently treated with TNF-alpha or an anti-Fas antibody (Jo2).
  • Key signaling events, including Akt phosphorylation, NF-kappa B activity, gene expression (Bcl-xL), and apoptosis, were assessed.

Main Results:

  • Both TNF-alpha and Jo2 induced Akt phosphorylation, which was blocked by the PI3K inhibitor LY-294002.
  • LY-294002 inhibited NF-kappa B activation and promoted apoptosis.
  • Dominant-negative Akt expression sensitized hepatocytes to apoptosis, while constitutively active Akt conferred protection.
  • Active Akt promoted NF-kappa B transcriptional activity and Bcl-xL induction.
  • Bcl-xL overexpression protected against Fas-mediated apoptosis.

Conclusions:

  • The PI3K/Akt pathway plays a significant protective role in Fas-mediated hepatocyte apoptosis.
  • This protection is dependent on NF-kappa B activation and partially mediated by the induction of Bcl-xL.
  • Understanding these pathways offers potential therapeutic targets for liver diseases involving apoptosis.

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