Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.
Identifieur interne : 000379 ( Main/Exploration ); précédent : 000378; suivant : 000380Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.
Auteurs : Milena Veskovic [Serbie] ; Dusan Mladenovic [Serbie] ; Marina Milenkovic [Serbie] ; Jelena Tosic [Serbie] ; Suncica Borozan [Serbie] ; Kristina Gopcevic [Serbie] ; Milica Labudovic-Borovic [Serbie] ; Vesna Dragutinovic [Serbie] ; Danijela Vucevic [Serbie] ; Bojan Jorgacevic [Serbie] ; Aleksandra Isakovic [Serbie] ; Vladimir Trajkovic [Serbie] ; Tatjana Radosavljevic [Serbie]Source :
- European journal of pharmacology [ 1879-0712 ] ; 2019.
Descripteurs français
- KwdFr :
- Agents gastro-intestinaux (pharmacologie), Agents gastro-intestinaux (usage thérapeutique), Animaux (MeSH), Autophagie (effets des médicaments et des substances chimiques), Autophagie (physiologie), Bétaïne (pharmacologie), Bétaïne (usage thérapeutique), Carence en choline (complications), Carence en choline (métabolisme), Inflammation (métabolisme), Inflammation (traitement médicamenteux), Inflammation (étiologie), Mâle (MeSH), Méthionine (déficit), Protéines proto-oncogènes c-akt (métabolisme), Souris (MeSH), Souris de lignée C57BL (MeSH), Stress oxydatif (effets des médicaments et des substances chimiques), Stress oxydatif (physiologie), Stéatose hépatique non alcoolique (métabolisme), Stéatose hépatique non alcoolique (traitement médicamenteux), Stéatose hépatique non alcoolique (étiologie), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques), Transduction du signal (physiologie).
- MESH :
- déficit : Carence en choline, Méthionine.
- effets des médicaments et des substances chimiques : Autophagie, Stress oxydatif, Transduction du signal.
- métabolisme : Carence en choline, Inflammation, Protéines proto-oncogènes c-akt, Stéatose hépatique non alcoolique, Sérine-thréonine kinases TOR.
- pharmacologie : Agents gastro-intestinaux, Bétaïne.
- physiologie : Autophagie, Stress oxydatif, Transduction du signal.
- traitement médicamenteux : Inflammation, Stéatose hépatique non alcoolique.
- usage thérapeutique : Agents gastro-intestinaux, Bétaïne.
- étiologie : Inflammation, Stéatose hépatique non alcoolique.
- Animaux, Mâle, Souris, Souris de lignée C57BL.
English descriptors
- KwdEn :
- Animals (MeSH), Autophagy (drug effects), Autophagy (physiology), Betaine (pharmacology), Betaine (therapeutic use), Choline Deficiency (complications), Choline Deficiency (metabolism), Gastrointestinal Agents (pharmacology), Gastrointestinal Agents (therapeutic use), Inflammation (drug therapy), Inflammation (etiology), Inflammation (metabolism), Male (MeSH), Methionine (deficiency), Mice (MeSH), Mice, Inbred C57BL (MeSH), Non-alcoholic Fatty Liver Disease (drug therapy), Non-alcoholic Fatty Liver Disease (etiology), Non-alcoholic Fatty Liver Disease (metabolism), Oxidative Stress (drug effects), Oxidative Stress (physiology), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (drug effects), Signal Transduction (physiology), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , deficiency : Methionine.
- chemical , metabolism : Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Betaine, Gastrointestinal Agents.
- complications : Choline Deficiency.
- drug effects : Autophagy, Oxidative Stress, Signal Transduction.
- drug therapy : Inflammation, Non-alcoholic Fatty Liver Disease.
- etiology : Inflammation, Non-alcoholic Fatty Liver Disease.
- metabolism : Choline Deficiency, Inflammation, Non-alcoholic Fatty Liver Disease.
- physiology : Autophagy, Oxidative Stress, Signal Transduction.
- chemical , therapeutic use : Betaine, Gastrointestinal Agents.
- Animals, Male, Mice, Mice, Inbred C57BL.
Abstract
We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Bax, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy.
DOI: 10.1016/j.ejphar.2019.01.043
PubMed: 30689995
Affiliations:
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Jelena" sort="Tosic, Jelena" uniqKey="Tosic J" first="Jelena" last="Tosic">Jelena Tosic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Borozan, Suncica" sort="Borozan, Suncica" uniqKey="Borozan S" first="Suncica" last="Borozan">Suncica Borozan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade</wicri:regionArea><wicri:noRegion>University of Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Gopcevic, Kristina" sort="Gopcevic, Kristina" uniqKey="Gopcevic K" first="Kristina" last="Gopcevic">Kristina Gopcevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Labudovic Borovic, Milica" sort="Labudovic Borovic, Milica" uniqKey="Labudovic Borovic M" first="Milica" last="Labudovic-Borovic">Milica Labudovic-Borovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Dragutinovic, Vesna" sort="Dragutinovic, Vesna" uniqKey="Dragutinovic V" first="Vesna" last="Dragutinovic">Vesna Dragutinovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Vucevic, Danijela" sort="Vucevic, Danijela" uniqKey="Vucevic D" first="Danijela" last="Vucevic">Danijela Vucevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Jorgacevic, Bojan" sort="Jorgacevic, Bojan" uniqKey="Jorgacevic B" first="Bojan" last="Jorgacevic">Bojan Jorgacevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Isakovic, Aleksandra" sort="Isakovic, Aleksandra" uniqKey="Isakovic A" first="Aleksandra" last="Isakovic">Aleksandra Isakovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vladimir.trajkovic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Radosavljevic, Tatjana" sort="Radosavljevic, Tatjana" uniqKey="Radosavljevic T" first="Tatjana" last="Radosavljevic">Tatjana Radosavljevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: tatjana.radosavljevic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:30689995</idno><idno type="pmid">30689995</idno><idno type="doi">10.1016/j.ejphar.2019.01.043</idno><idno type="wicri:Area/Main/Corpus">000360</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000360</idno><idno type="wicri:Area/Main/Curation">000360</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000360</idno><idno type="wicri:Area/Main/Exploration">000360</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.</title><author><name sortKey="Veskovic, Milena" sort="Veskovic, Milena" uniqKey="Veskovic M" first="Milena" last="Veskovic">Milena Veskovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Mladenovic, Dusan" sort="Mladenovic, Dusan" uniqKey="Mladenovic D" first="Dusan" last="Mladenovic">Dusan Mladenovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Milenkovic, Marina" sort="Milenkovic, Marina" uniqKey="Milenkovic M" first="Marina" last="Milenkovic">Marina Milenkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Tosic, Jelena" sort="Tosic, Jelena" uniqKey="Tosic J" first="Jelena" last="Tosic">Jelena Tosic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Borozan, Suncica" sort="Borozan, Suncica" uniqKey="Borozan S" first="Suncica" last="Borozan">Suncica Borozan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade</wicri:regionArea><wicri:noRegion>University of Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Gopcevic, Kristina" sort="Gopcevic, Kristina" uniqKey="Gopcevic K" first="Kristina" last="Gopcevic">Kristina Gopcevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Labudovic Borovic, Milica" sort="Labudovic Borovic, Milica" uniqKey="Labudovic Borovic M" first="Milica" last="Labudovic-Borovic">Milica Labudovic-Borovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Dragutinovic, Vesna" sort="Dragutinovic, Vesna" uniqKey="Dragutinovic V" first="Vesna" last="Dragutinovic">Vesna Dragutinovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Vucevic, Danijela" sort="Vucevic, Danijela" uniqKey="Vucevic D" first="Danijela" last="Vucevic">Danijela Vucevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Jorgacevic, Bojan" sort="Jorgacevic, Bojan" uniqKey="Jorgacevic B" first="Bojan" last="Jorgacevic">Bojan Jorgacevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Isakovic, Aleksandra" sort="Isakovic, Aleksandra" uniqKey="Isakovic A" first="Aleksandra" last="Isakovic">Aleksandra Isakovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vladimir.trajkovic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Radosavljevic, Tatjana" sort="Radosavljevic, Tatjana" uniqKey="Radosavljevic T" first="Tatjana" last="Radosavljevic">Tatjana Radosavljevic</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: tatjana.radosavljevic@med.bg.ac.rs.</nlm:affiliation><country xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation></author></analytic><series><title level="j">European journal of pharmacology</title><idno type="eISSN">1879-0712</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Autophagy (drug effects)</term><term>Autophagy (physiology)</term><term>Betaine (pharmacology)</term><term>Betaine (therapeutic use)</term><term>Choline Deficiency (complications)</term><term>Choline Deficiency (metabolism)</term><term>Gastrointestinal Agents (pharmacology)</term><term>Gastrointestinal Agents (therapeutic use)</term><term>Inflammation (drug therapy)</term><term>Inflammation (etiology)</term><term>Inflammation (metabolism)</term><term>Male (MeSH)</term><term>Methionine (deficiency)</term><term>Mice (MeSH)</term><term>Mice, Inbred C57BL (MeSH)</term><term>Non-alcoholic Fatty Liver Disease (drug therapy)</term><term>Non-alcoholic Fatty Liver Disease (etiology)</term><term>Non-alcoholic Fatty Liver Disease (metabolism)</term><term>Oxidative Stress (drug effects)</term><term>Oxidative Stress (physiology)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Signal Transduction (drug effects)</term><term>Signal Transduction (physiology)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents gastro-intestinaux (pharmacologie)</term><term>Agents gastro-intestinaux (usage thérapeutique)</term><term>Animaux (MeSH)</term><term>Autophagie (effets des médicaments et des substances chimiques)</term><term>Autophagie (physiologie)</term><term>Bétaïne (pharmacologie)</term><term>Bétaïne (usage thérapeutique)</term><term>Carence en choline (complications)</term><term>Carence en choline (métabolisme)</term><term>Inflammation (métabolisme)</term><term>Inflammation (traitement médicamenteux)</term><term>Inflammation (étiologie)</term><term>Mâle (MeSH)</term><term>Méthionine (déficit)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Souris (MeSH)</term><term>Souris de lignée C57BL (MeSH)</term><term>Stress oxydatif (effets des médicaments et des substances chimiques)</term><term>Stress oxydatif (physiologie)</term><term>Stéatose hépatique non alcoolique (métabolisme)</term><term>Stéatose hépatique non alcoolique (traitement médicamenteux)</term><term>Stéatose hépatique non alcoolique (étiologie)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term><term>Transduction du signal (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Methionine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Betaine</term><term>Gastrointestinal Agents</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Choline Deficiency</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Oxidative Stress</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Inflammation</term><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Carence en choline</term><term>Méthionine</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Autophagie</term><term>Stress oxydatif</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Inflammation</term><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Choline Deficiency</term><term>Inflammation</term><term>Non-alcoholic Fatty Liver Disease</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carence en choline</term><term>Inflammation</term><term>Protéines proto-oncogènes c-akt</term><term>Stéatose hépatique non alcoolique</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents gastro-intestinaux</term><term>Bétaïne</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Autophagie</term><term>Stress oxydatif</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Autophagy</term><term>Oxidative Stress</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Betaine</term><term>Gastrointestinal Agents</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Inflammation</term><term>Stéatose hépatique non alcoolique</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Agents gastro-intestinaux</term><term>Bétaïne</term></keywords><keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Inflammation</term><term>Stéatose hépatique non alcoolique</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Mâle</term><term>Souris</term><term>Souris de lignée C57BL</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Bax, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30689995</PMID><DateCompleted><Year>2019</Year><Month>06</Month><Day>06</Day></DateCompleted><DateRevised><Year>2019</Year><Month>06</Month><Day>06</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1879-0712</ISSN><JournalIssue CitedMedium="Internet"><Volume>848</Volume><PubDate><Year>2019</Year><Month>Apr</Month><Day>05</Day></PubDate></JournalIssue><Title>European journal of pharmacology</Title><ISOAbbreviation>Eur J Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.</ArticleTitle><Pagination><MedlinePgn>39-48</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0014-2999(19)30063-9</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejphar.2019.01.043</ELocationID><Abstract><AbstractText>We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Bax, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy.</AbstractText><CopyrightInformation>Copyright © 2019 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Veskovic</LastName><ForeName>Milena</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mladenovic</LastName><ForeName>Dusan</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Milenkovic</LastName><ForeName>Marina</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tosic</LastName><ForeName>Jelena</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Borozan</LastName><ForeName>Suncica</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gopcevic</LastName><ForeName>Kristina</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Labudovic-Borovic</LastName><ForeName>Milica</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dragutinovic</LastName><ForeName>Vesna</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vucevic</LastName><ForeName>Danijela</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jorgacevic</LastName><ForeName>Bojan</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Isakovic</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trajkovic</LastName><ForeName>Vladimir</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vladimir.trajkovic@med.bg.ac.rs.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radosavljevic</LastName><ForeName>Tatjana</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: tatjana.radosavljevic@med.bg.ac.rs.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>01</Month><Day>25</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Eur J Pharmacol</MedlineTA><NlmUniqueID>1254354</NlmUniqueID><ISSNLinking>0014-2999</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005765">Gastrointestinal Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>3SCV180C9W</RegistryNumber><NameOfSubstance UI="D001622">Betaine</NameOfSubstance></Chemical><Chemical><RegistryNumber>AE28F7PNPL</RegistryNumber><NameOfSubstance UI="D008715">Methionine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546843">mTOR protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001622" MajorTopicYN="N">Betaine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002796" MajorTopicYN="N">Choline Deficiency</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005765" MajorTopicYN="N">Gastrointestinal Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007249" MajorTopicYN="N">Inflammation</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008715" MajorTopicYN="N">Methionine</DescriptorName><QualifierName UI="Q000172" MajorTopicYN="Y">deficiency</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D065626" MajorTopicYN="N">Non-alcoholic Fatty Liver Disease</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018384" MajorTopicYN="N">Oxidative Stress</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Apoptosis</Keyword><Keyword MajorTopicYN="N">Autophagy</Keyword><Keyword MajorTopicYN="N">Betaine</Keyword><Keyword MajorTopicYN="N">Inflammation</Keyword><Keyword MajorTopicYN="N">Non-alcoholic fatty liver disease</Keyword><Keyword MajorTopicYN="N">Oxidative stress</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>12</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>01</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>01</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>1</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>6</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>1</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30689995</ArticleId><ArticleId IdType="pii">S0014-2999(19)30063-9</ArticleId><ArticleId IdType="doi">10.1016/j.ejphar.2019.01.043</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Serbie</li></country></list><tree><country name="Serbie"><noRegion><name sortKey="Veskovic, Milena" sort="Veskovic, Milena" uniqKey="Veskovic M" first="Milena" last="Veskovic">Milena Veskovic</name></noRegion><name sortKey="Borozan, Suncica" sort="Borozan, Suncica" uniqKey="Borozan S" first="Suncica" last="Borozan">Suncica Borozan</name><name sortKey="Dragutinovic, Vesna" sort="Dragutinovic, Vesna" uniqKey="Dragutinovic V" first="Vesna" last="Dragutinovic">Vesna Dragutinovic</name><name sortKey="Gopcevic, Kristina" sort="Gopcevic, Kristina" uniqKey="Gopcevic K" first="Kristina" last="Gopcevic">Kristina Gopcevic</name><name sortKey="Isakovic, Aleksandra" sort="Isakovic, Aleksandra" uniqKey="Isakovic A" first="Aleksandra" last="Isakovic">Aleksandra Isakovic</name><name sortKey="Jorgacevic, Bojan" sort="Jorgacevic, Bojan" uniqKey="Jorgacevic B" first="Bojan" last="Jorgacevic">Bojan Jorgacevic</name><name sortKey="Labudovic Borovic, Milica" sort="Labudovic Borovic, Milica" uniqKey="Labudovic Borovic M" first="Milica" last="Labudovic-Borovic">Milica Labudovic-Borovic</name><name sortKey="Milenkovic, Marina" sort="Milenkovic, Marina" uniqKey="Milenkovic M" first="Marina" last="Milenkovic">Marina Milenkovic</name><name sortKey="Mladenovic, Dusan" sort="Mladenovic, Dusan" uniqKey="Mladenovic D" first="Dusan" last="Mladenovic">Dusan Mladenovic</name><name sortKey="Radosavljevic, Tatjana" sort="Radosavljevic, Tatjana" uniqKey="Radosavljevic T" first="Tatjana" last="Radosavljevic">Tatjana Radosavljevic</name><name sortKey="Tosic, Jelena" sort="Tosic, Jelena" uniqKey="Tosic J" first="Jelena" last="Tosic">Jelena Tosic</name><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><name sortKey="Vucevic, Danijela" sort="Vucevic, Danijela" uniqKey="Vucevic D" first="Danijela" last="Vucevic">Danijela Vucevic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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