Thymosin beta 4 alleviates non-alcoholic fatty liver by inhibiting ferroptosis via up-regulation of GPX4.
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| Abstract |
Thymosin beta 4 (Tβ4) can improve the liver fibrosis and reduce inflammation, while the role of Tβ4 in non-alcoholic fatty liver disease (NAFLD) whether mediated by ferroptosis remains unclear. A rat model of NAFLD was established on a high-fat diet (HFD), and rats were assigned ferroptosis inducer erastin and inhibitor Ferrostatin 1 (Fer-1). Subsequently, histopathology of the liver and the expression of ferroptosis-related genes in rat liver were detected. The steatosis of LO2 cells was induced by palmitic acid (PA) to reproduce the results of the rat experiment. The small interfering RNA (siRNA) was used to interfere with GPX4 expression to explore the influence on Tβ4 function. Tβ4 improved the inflammation, biochemical and lipid metabolism indexes, increased the antioxidant level, and inhibited abnormal accumulation of intracellular reactive oxygen species in HFD-induced NAFLD rats. Also, Tβ4 improved PA-induced LO2 damage and inhibited apoptosis of PA-induced LO2 cells. Both in vivo and in vitro, Tβ4 regulated expression of genes associated with ferroptosis, and Fer-1 treatment exaggerated the above effects of Tβ4, while erastin attenuated the protective effect of Tβ4. Moreover, siRNA GPX4 attenuated the protective effect of Tβ4 on the rat liver and on the mitochondrial membrane integrity of LO2 cells. Interfered expression of GPX4 with siRNA also regulated the expression of Bcl-2, Bax, Caspase-3 and SOD1, which attenuated therapeutic effect of Tβ4 on rat liver and LO2 cells. This study revealed that Tβ4 protects hepatocytes by inhibiting the GPX4-mediated ferroptosis pathway, which provides a new strategy and target for the treatment of NAFLD.
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| Authors | Zixin Zhu, Ya Zhang, Xinhao Huang, Li Can, Xueke Zhao, Yinghui Wang, Jing Xue, Mingliang Cheng, Lili Zhu |
| Journal | European journal of pharmacology (Eur J Pharmacol) Vol. 908 Pg. 174351 (Oct 05 2021) ISSN: 1879-0712 [Electronic] Netherlands |
| PMID | 34280397 (Publication Type: Journal Article) |
| Copyright | Copyright © 2021 Elsevier B.V. All rights reserved. |
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