PMID- 30689995 OWN - NLM STAT- MEDLINE DCOM- 20190606 LR - 20211204 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 848 DP - 2019 Apr 5 TI - Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. PG - 39-48 LID - S0014-2999(19)30063-9 [pii] LID - 10.1016/j.ejphar.2019.01.043 [doi] AB - 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. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Veskovic, Milena AU - Veskovic M AD - Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Mladenovic, Dusan AU - Mladenovic D AD - Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Milenkovic, Marina AU - Milenkovic M AD - Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Tosic, Jelena AU - Tosic J AD - Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Borozan, Suncica AU - Borozan S AD - Department of Chemistry, Faculty of Veterinary Medicine, University of Belgrade, Serbia. FAU - Gopcevic, Kristina AU - Gopcevic K AD - Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Labudovic-Borovic, Milica AU - Labudovic-Borovic M AD - Institute of Histology and Embriology, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Dragutinovic, Vesna AU - Dragutinovic V AD - Institute of Medical Chemistry, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Vucevic, Danijela AU - Vucevic D AD - Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Jorgacevic, Bojan AU - Jorgacevic B AD - Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Isakovic, Aleksandra AU - Isakovic A AD - Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia. FAU - Trajkovic, Vladimir AU - Trajkovic V AD - Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vladimir.trajkovic@med.bg.ac.rs. FAU - Radosavljevic, Tatjana AU - Radosavljevic T AD - Institute of Pathophysiology "Ljubodrag Buba Mihailovic", School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: tatjana.radosavljevic@med.bg.ac.rs. LA - eng PT - Journal Article DEP - 20190125 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Gastrointestinal Agents) RN - 3SCV180C9W (Betaine) RN - AE28F7PNPL (Methionine) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Autophagy/drug effects/physiology MH - Betaine/pharmacology/*therapeutic use MH - Choline Deficiency/complications/*metabolism MH - Gastrointestinal Agents/pharmacology/therapeutic use MH - Inflammation/drug therapy/etiology/metabolism MH - Male MH - Methionine/*deficiency MH - Mice MH - Mice, Inbred C57BL MH - Non-alcoholic Fatty Liver Disease/drug therapy/etiology/*metabolism MH - Oxidative Stress/drug effects/*physiology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Signal Transduction/drug effects/physiology MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Betaine OT - Inflammation OT - Non-alcoholic fatty liver disease OT - Oxidative stress EDAT- 2019/01/29 06:00 MHDA- 2019/06/07 06:00 CRDT- 2019/01/29 06:00 PHST- 2018/12/07 00:00 [received] PHST- 2019/01/18 00:00 [revised] PHST- 2019/01/24 00:00 [accepted] PHST- 2019/01/29 06:00 [pubmed] PHST- 2019/06/07 06:00 [medline] PHST- 2019/01/29 06:00 [entrez] AID - S0014-2999(19)30063-9 [pii] AID - 10.1016/j.ejphar.2019.01.043 [doi] PST - ppublish SO - Eur J Pharmacol. 2019 Apr 5;848:39-48. doi: 10.1016/j.ejphar.2019.01.043. Epub 2019 Jan 25.