Chinese Journal of Tissue Engineering Research ›› 2023, Vol. 27 ›› Issue (17): 2681-2686.doi: 10.12307/2023.423

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Ferroptosis is involved in the pathogenesis of liver injury induced by high methionine diet in ApoE-/- mice

Li Yuanyuan1, Sun Yue1, Bao Rui1, Chang Sirong1, Wang Meng1, Yu Mengxue1, Yang Anning2, Liu Zhihong1   

  1. 1School of Public Health and Management, 2School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
  • Received:2022-06-06 Accepted:2022-07-21 Online:2023-06-18 Published:2022-10-24
  • Contact: Liu Zhihong, MD, Professor, School of Public Health and Management, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China Yang Anning, MD, Associate professor, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
  • About author:Li Yuanyuan, Master candidate, School of Public Health and Management, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
  • Supported by:
    the National Natural Science Foundation of China, Nos. 81960018 (to LZH), 82060264 (to SY), and 82160088 (to YAN); Key R&D Project of the Department of Science and Technology of Ningxia Hui Autonomous Region, Nos. 2020BEG03008 (to SY), 2020BFH02003 (to YAN), and 2021BEG02030 (to LZH) 

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Abstract: BACKGROUND: Homocysteine can promote the occurrence of liver injury through oxidative stress, inflammatory response, and endoplasmic reticulum stress. High methionine diet-induced apolipoprotein gene knockout (ApoE-/-) can induce liver injury and increase in vivo homocysteine level in mice. Ferroptosis is a cellular regulatory death pathway that depends on intracellular iron and causes excessive accumulation of lipid peroxides. However, whether it is involved in the formation of liver injury induced by high methionine diet needs to be further studied and discussed.
OBJECTIVE: To explore the role of ferroptosis in hyperhomocysteine-induced liver injury in ApoE-/- mice. 
METHODS: Twelve ApoE-/- mice aged 6 to 8 weeks were randomly divided into control group and high methionine group (n=6 per group), and fed with normal diet and high methionine diet for 13.5 weeks. Liver injury in ApoE-/- mice was evaluated by pathological observation and detection of aspartate aminotransferase and alanine aminotransferase activity in liver tissue. Iron ion concentration in liver tissue of mice was tested by tissue iron detection kit. Malondialdehyde content and fluorescence intensity were detected to evaluate the degree of lipid peroxidation in the liver tissue of mice. Real-time fluorescence quantitative PCR and western blot were performed to determine the expression of P53 and glutathione peroxidase 4 at mRNA and protein levels in the liver tissue. 
RESULTS AND CONCLUSION: Compared with the control group, a large number of liver cells in the high methionine diet group were found to have the typical histopathological changes of liver injury, such as disordered arrangement of liver cells, enlarged space, and loose cytoplasm. Compared with the control group, the activities of aspartate aminotransferase and alanine aminotransferase were significantly increased (P < 0.01). Meanwhile, the concentration of iron ions (P < 0.01), malondialdehyde content (P < 0.01), and fluorescence intensity in liver tissue were also significantly increased in the high methionine diet group. Real-time fluorescence quantitative PCR and western blot results showed that the expression level of glutathione peroxidase 4 was decreased (P < 0.01) and the expression of P53 was increased (P < 0.05) in ApoE-/- mice in the high methionine diet group. These findings indicate that ferroptosis is involved in the pathogenesis of liver injury in ApoE-/- mice induced by high methionine diet.

Key words: liver injury, ferroptosis, lipid peroxidation, hyperhomocysteinemia, malondialdehyde

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