title: Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation.
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.
authors.affiliation: Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic; monika.cahova@ikem.cz.
authors.forename: Monika
authors.initials: M
authors.lastname: Cahova
authors.affiliation: 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;
authors.forename: Eliska
authors.initials: E
authors.lastname: Palenickova
authors.affiliation: Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic;
authors.forename: Helena
authors.initials: H
authors.lastname: Dankova
authors.affiliation: Clinical and Transplant Pathology Department, Charles University, Prague, Czech Republic;
authors.forename: Eva
authors.initials: E
authors.lastname: Sticova
authors.affiliation: Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic;
authors.forename: Martin
authors.initials: M
authors.lastname: Burian
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic;
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Drahota
authors.affiliation: Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Cervinkova
authors.affiliation: Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic;
authors.forename: Otto
authors.initials: O
authors.lastname: Kucera
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Gladkova
authors.affiliation: Institute of Inorganic Chemistry Academy of Science CR, Husinec-Rez, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Stopka
authors.affiliation: Institute of Inorganic Chemistry Academy of Science CR, Husinec-Rez, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Krizova
authors.affiliation: Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic;
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Papackova
authors.affiliation: Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic;
authors.forename: Olena
authors.initials: O
authors.lastname: Oliyarnyk
authors.affiliation: Center for Experimental Medicine, Department of Metabolism and Diabetes, Charles University, Prague, Czech Republic;
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdova
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D008687:Metformin
keywords: 31P MR spectroscopy; liver injury; metformin; mitochondrial respiration; oxidative stress