Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease
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2019
Authors
Vesković, MilenaMladenović, Dušan
Milenković, Marina
Tosić, Jelena
Borozan, Sunčica
Gopcević, Kristina
Labudović-Borović, Milica
Dragutinović, Vesna
Vučević, Dragana
Jorgacević, Bojan
Isaković, Aleksandra
Trajković, Vladimir
Radosavljević, Tatjana
Article (Published version)
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Show full item recordAbstract
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 Box, 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.
Keywords:
Betaine / Non-alcoholic fatty liver disease / Oxidative stress / Apoptosis / Inflammation / AutophagySource:
European Journal of Pharmacology, 2019, 848, 39-48Publisher:
- Elsevier Science Bv, Amsterdam
Funding / projects:
- The role of neuroendocrine-inflammatory axis in the pathogenesis of non-alcoholic fatty liver disease (RS-MESTD-Basic Research (BR or ON)-175015)
- Modulation of intracellular energy balance-controlling signalling pathways in therapy of cancer and neuro-immuno-endocrine disorders (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41025)
DOI: 10.1016/j.ejphar.2019.01.043
ISSN: 0014-2999
PubMed: 30689995
WoS: 000459483200005
Scopus: 2-s2.0-85060871124
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Fakultet veterinarske medicineTY - JOUR AU - Vesković, Milena AU - Mladenović, Dušan AU - Milenković, Marina AU - Tosić, Jelena AU - Borozan, Sunčica AU - Gopcević, Kristina AU - Labudović-Borović, Milica AU - Dragutinović, Vesna AU - Vučević, Dragana AU - Jorgacević, Bojan AU - Isaković, Aleksandra AU - Trajković, Vladimir AU - Radosavljević, Tatjana PY - 2019 UR - https://vet-erinar.vet.bg.ac.rs/handle/123456789/1727 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 Box, 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. PB - Elsevier Science Bv, Amsterdam T2 - European Journal of Pharmacology T1 - Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease VL - 848 SP - 39 EP - 48 DO - 10.1016/j.ejphar.2019.01.043 ER -
@article{ author = "Vesković, Milena and Mladenović, Dušan and Milenković, Marina and Tosić, Jelena and Borozan, Sunčica and Gopcević, Kristina and Labudović-Borović, Milica and Dragutinović, Vesna and Vučević, Dragana and Jorgacević, Bojan and Isaković, Aleksandra and Trajković, Vladimir and Radosavljević, Tatjana", year = "2019", 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 Box, 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.", publisher = "Elsevier Science Bv, Amsterdam", journal = "European Journal of Pharmacology", title = "Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease", volume = "848", pages = "39-48", doi = "10.1016/j.ejphar.2019.01.043" }
Vesković, M., Mladenović, D., Milenković, M., Tosić, J., Borozan, S., Gopcević, K., Labudović-Borović, M., Dragutinović, V., Vučević, D., Jorgacević, B., Isaković, A., Trajković, V.,& Radosavljević, T.. (2019). Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. in European Journal of Pharmacology Elsevier Science Bv, Amsterdam., 848, 39-48. https://doi.org/10.1016/j.ejphar.2019.01.043
Vesković M, Mladenović D, Milenković M, Tosić J, Borozan S, Gopcević K, Labudović-Borović M, Dragutinović V, Vučević D, Jorgacević B, Isaković A, Trajković V, Radosavljević T. Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease. in European Journal of Pharmacology. 2019;848:39-48. doi:10.1016/j.ejphar.2019.01.043 .
Vesković, Milena, Mladenović, Dušan, Milenković, Marina, Tosić, Jelena, Borozan, Sunčica, Gopcević, Kristina, Labudović-Borović, Milica, Dragutinović, Vesna, Vučević, Dragana, Jorgacević, Bojan, Isaković, Aleksandra, Trajković, Vladimir, Radosavljević, Tatjana, "Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease" in European Journal of Pharmacology, 848 (2019):39-48, https://doi.org/10.1016/j.ejphar.2019.01.043 . .