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Therapeutic role of FNDC5/irisin in attenuating liver fibrosis via inhibiting release of hepatic stellate cell-derived exosomes

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Abstract

Objective

Cleavage of fibronectin type III domain-containing protein 5 (FNDC5), a membrane-bound precursor protein, would cleave into a myokine, irisin, which is also expressed in the liver. FNDC5/Irisin has been reported to play a critical role in maintaining glucose and lipid homeostasis in the liver and in combating liver fibrosis. Recently, several studies have shown that extracellular vesicles (EVs) derived from hepatic stellate cells (HSCs) could modulate liver fibrosis; however, there is a large gap in understanding whether inhibition of fibrogenic EVs derived from HSCs could alleviate the progression of liver fibrosis. Here, we investigated the role of FNDC5/irisin in liver fibrosis and the mechanism of its inhibitory role in the release of HSC-derived fibrogenic EVs.

Methods

Experiments were performed in wild-type and FNDC5−/− mice, primary mouse HSCs, and human hepatic stellate cell line (LX2). Mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL) to induce liver fibrosis. EVs derived from HSCs were purified and injected intraperitoneally into mice.

Results

Our results showed that FNDC5 deficiency exacerbated CCl4-induced liver fibrosis and activation of HSCs in mice. Moreover, fibrogenic EVs derived from PDGF-BB-treated HSCs promoted HSC migration in vitro and liver fibrosis in vivo. However, administration of irisin, a cleavage of FNDC5, inhibited the release of fibrogenic EVs and activation of HSCs by promoting ubiquitylation degradation of Rab27b. In vivo, the promoting role of HSC-derived fibrogenic EVs in liver fibrosis was also reversed by irisin.

Conclusion

All these results demonstrate that FNDC5/irisin is a novel therapeutic agent for chronic liver fibrosis.

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Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

Doctor Start-up Fund of Affiliated Hospital of Guizhou Medical University, gyfybsky-2022–15; Science and Technology Planning Project of Guizhou Province (Basic of Guizhou Science and Technology Cooperation -ZK[2023] Key Project[038]).

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Authors and Affiliations

  1. Department of Medical Imaging, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, Guizhou, China

    Xin Liao, Yilin Luo, Fang Gu, Wen Song, Xin Nie & Qin Yang

  2. Department of Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550000, Guizhou, China

    Qin Yang

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  1. Xin Liao
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  2. Yilin Luo
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  3. Fang Gu
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  4. Wen Song
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Contributions

Drafting of the manuscript: XL. Research conception and design: FG, YL. Data analysis and interpretation: WS, XN. Statistical analysis: XL, YL. Literature retrieval: FG, XL. Critical revision of the manuscript: QY. Approval of the final manuscript: all authors.

Corresponding author

Correspondence to Qin Yang.

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Conflict of interest

Xin Liao, Yilin Luo, Fang Gu, Wen Song, Xin Nie, Qin Yang declare that they have no competing interests.

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Protocols for in vivo experiments were approved by the Animal Welfare and Use Committee of Guizhou Medical University.

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Liao, X., Luo, Y., Gu, F. et al. Therapeutic role of FNDC5/irisin in attenuating liver fibrosis via inhibiting release of hepatic stellate cell-derived exosomes. Hepatol Int 17, 1659–1671 (2023). https://doi.org/10.1007/s12072-023-10523-y

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  • DOI: https://doi.org/10.1007/s12072-023-10523-y

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