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Am J Physiol Gastrointest Liver Physiol. 2015 Jul 15;309(2):G100-11. doi: 10.1152/ajpgi.00329.2014. Epub 2015 Jun 4.

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation.

Author information

1
Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic; monika.cahova@ikem.cz.
2
Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic; Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic;
3
Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic;
4
Clinical and Transplant Pathology Department, Charles University, Prague, Czech Republic;
5
Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic;
6
Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic;
7
Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
8
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and.
9
Institute of Inorganic Chemistry Academy of Science CR, Husinec-Rez, Czech Republic.

Abstract

Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt(-1)·day(-1)). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH- and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-α, TLR4, IL-1β, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation.

KEYWORDS:

31P MR spectroscopy; liver injury; metformin; mitochondrial respiration; oxidative stress

PMID:
26045616
DOI:
10.1152/ajpgi.00329.2014
[Indexed for MEDLINE]
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