Metformin Protects Rat Hepatocytes against Bile Acid-Induced Apoptosis

Titia E. Woudenberg-Vrenken, Laura Conde de la Rosa, Manon Buist-Homan, Klaas Nico Faber, Han Moshage*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)
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Abstract

Background: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death.

Aim: To evaluate the effects of metformin on hepatocyte cell death.

Methods: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNF alpha in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively.

Results: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNF alpha/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-kappa B activation.

Conclusion: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.

Original languageEnglish
Article numbere71773
Number of pages10
JournalPLoS ONE
Volume8
Issue number8
DOIs
Publication statusPublished - 12-Aug-2013

Keywords

  • KAPPA-B ACTIVATION
  • FATTY LIVER-DISEASE
  • NONALCOHOLIC STEATOHEPATITIS
  • KINASE ACTIVATION
  • SIGNALING PATHWAY
  • MAMMALIAN TARGET
  • DEATH RECEPTORS
  • AMPK
  • CELLS
  • MTOR

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