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Metformin protects rat hepatocytes against bile acid-induced apoptosis

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 in...

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Published in:PloS one 2013-08, Vol.8 (8), p.e71773
Main Authors: Woudenberg-Vrenken, Titia E, Conde de la Rosa, Laura, Buist-Homan, Manon, Faber, Klaas Nico, Moshage, Han
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Conde de la Rosa, Laura
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Moshage, Han
description 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. To evaluate the effects of metformin on hepatocyte cell death. 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. 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. Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.
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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. To evaluate the effects of metformin on hepatocyte cell death. 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. 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. 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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. To evaluate the effects of metformin on hepatocyte cell death. 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. 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. 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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. Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23951244</pmid><doi>10.1371/journal.pone.0071773</doi><tpages>e71773</tpages><oa>free_for_read</oa></addata></record>
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1932-6203
language eng
recordid cdi_plos_journals_1430421024
source Publicly Available Content Database; PubMed Central
subjects 1-Phosphatidylinositol 3-kinase
Acids
Acridine orange
Actinomycin
Activation
AKT protein
AMP
AMP-activated protein kinase
AMP-Activated Protein Kinases - metabolism
Animals
Antidiabetics
Apoptosis
Apoptosis - drug effects
Bile
Bile Acids and Salts - metabolism
Bile Acids and Salts - pharmacology
Biology
Caspase
Caspase 3 - metabolism
Cell death
Cell Membrane - metabolism
Deoxycholic acid
Diabetes mellitus
Diabetes therapy
Dose-Response Relationship, Drug
Fatty liver
Glycochenodeoxycholic Acid - metabolism
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - pathology
Hypoglycemic Agents - pharmacology
Kinases
Laboratories
Liver
Liver diseases
Male
Medical treatment
Medicine
Metformin
Metformin - pharmacology
Mortality
Necrosis - drug therapy
NF-kappa B - metabolism
NF-κB protein
Pharmacology
Phosphatidylinositol 3-Kinases - metabolism
Protein kinases
Proto-Oncogene Proteins c-akt - metabolism
Rapamycin
Rats
Rodents
Signal Transduction
Signaling
Staining
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tumor necrosis factor
Tumor necrosis factor-α
title Metformin protects rat hepatocytes against bile acid-induced apoptosis
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