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The role of ferroptosis in chronic intermittent hypoxia-induced liver injury in rats

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Abstract

Purpose

Obstructive sleep apnea (OSA) has been related to an increased risk of liver injury. Ferroptosis is a form of programmed cell death implicated in multiple physiological and pathological processes. This study aimed to explore the role of ferroptosis in chronic intermittent hypoxia (CIH)-induced liver injury as well as to uncover the underlying mechanisms using a CIH rat model.

Methods

Fourteen male Sprague-Dawley rats were randomly allocated to either the normal control (NC) (n = 7) or the CIH group (n = 7). Rats were exposed to intermittent hypoxia for 8 weeks in CIH group. Liver function, histological changes, and markers of oxidative stress were evaluated. The protein levels of hypoxia-inducible factor-1α, nuclear factor E2-related factor 2 (Nrf2), Acyl-CoA synthetase long-chain family member 4 (ACSL4), and glutathione peroxidase 4 (GPX4) in liver were examined by Western blot analysis.

Results

CIH treatment caused significant increase of serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde (MDA). Liver MDA was significantly higher in CIH group than that in NC group. Histology showed that CIH treatment induced discernible swelled, disordered hepatocytes, necrosis, and infiltrated inflammatory cells. CIH treatment significantly reduced the expression of GPX4, while markedly up-regulated expression of ACSL4, indicating elevation in hepatic ferroptosis. In addition, the protein expression of Nrf2 in CIH group was significantly lower than that in NC group.

Conclusions

Ferroptosis played a crucial role in CIH-induced liver injury. The hepatic ferroptosis in CIH rat model might be mediated by the dysregulation of Nrf2. This highlights a potential therapeutic target for the treatment of OSA-related liver injury.

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Funding

This work was supported by National Natural Science Foundation of China (81870074), National Natural Science Foundation of China (81900088), and Startup Fund for scientific research from Fujian Medical University (2017XQ1117).

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Author notes

  1. Li-Da Chen and Run-Hua Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, No 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People’s Republic of China

    Li-Da Chen, Meng-Xue Chen, Ai-Ming Zeng & Qi-Chang Lin

  2. Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China

    Li-Da Chen

  3. College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People’s Republic of China

    Run-Hua Wu, Gui-feng Zhuo, Feng-Sheng Xu & Ran Liao

  4. Department of Pathology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China

    Yu-Zhen Huang

  5. Fujian Provincial Sleep-Disordered Breathing Clinic Center, Fuzhou, Fujian Province, People’s Republic of China

    Qi-Chang Lin

  6. Laboratory of Respiratory Disease of the Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China

    Qi-Chang Lin

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  1. Li-Da Chen
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Correspondence to Qi-Chang Lin.

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Chen, LD., Wu, RH., Huang, YZ. et al. The role of ferroptosis in chronic intermittent hypoxia-induced liver injury in rats. Sleep Breath 24, 1767–1773 (2020). https://doi.org/10.1007/s11325-020-02091-4

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  • DOI: https://doi.org/10.1007/s11325-020-02091-4

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