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

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2015-07, Vol.309 (2), p.G100-G111
• Main Authors: Cahova, Monika, Palenickova, Eliska, Dankova, Helena, Sticova, Eva, Burian, Martin, Drahota, Zdenek, Cervinkova, Zuzana, Kucera, Otto, Gladkova, Christina, Stopka, Pavel, Krizova, Jana, Papackova, Zuzana, Oliyarnyk, Olena, Kazdova, Ludmila
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Antioxidants; Antioxidants - pharmacology; Apoptosis - drug effects; Cytoprotection; Diet, High-Fat; Disease Models, Animal; DNA damage; Energy Metabolism - drug effects; Enzymes; Inflammation Mediators - metabolism; Lipid Peroxidation - drug effects; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver diseases; Male; Metformin - pharmacology; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondria, Liver - pathology; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oxidative stress; Oxidative Stress - drug effects; Physiology; Rats, Wistar; Reactive Oxygen Species - metabolism; Reperfusion Injury - etiology; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Time Factors
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00329.2014

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.