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Metformin protects rat hepatocytes against bile acid-induced apoptosis.

AbstractBACKGROUND:
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 TNFα 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 TNFα/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-κB activation.
CONCLUSION:
Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.
AuthorsTitia E Woudenberg-Vrenken, Laura Conde de la Rosa, Manon Buist-Homan, Klaas Nico Faber, Han Moshage
JournalPloS one (PLoS One) Vol. 8 Issue 8 Pg. e71773 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23951244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bile Acids and Salts
  • Hypoglycemic Agents
  • NF-kappa B
  • Glycochenodeoxycholic Acid
  • Metformin
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Caspase 3
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Bile Acids and Salts (metabolism, pharmacology)
  • Caspase 3 (metabolism)
  • Cell Membrane (metabolism)
  • Dose-Response Relationship, Drug
  • Glycochenodeoxycholic Acid (metabolism)
  • Hepatocytes (drug effects, metabolism, pathology)
  • Hypoglycemic Agents (pharmacology)
  • Male
  • Metformin (pharmacology)
  • NF-kappa B (metabolism)
  • Necrosis (drug therapy)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases (metabolism)

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