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FGF21 ameliorates hepatic fibrosis by multiple mechanisms

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Abstract

Background

Previous study reports that fibroblast growth factor 21 (FGF21) could ameliorate hepatic fibrosis, but its mechanisms have not been fully investigated.

Methods and results

In this study, three models were used to investigate the mechanism by which FGF21 alleviates liver fibrosis. Hepatic fibrosis animal models were respectively induced by CCL4 and dimethylnitrosamine. Our results demonstrated that liver index and liver function were deteriorated in both models. Hematoxylin and eosin and Masson’s staining showed that the damaged tissue architectonics were observed in the mice of both models. Treatment with FGF21 significantly ameliorated these changes. ELISA analysis showed that the serum levels of IL-1β, IL-6 and TNF-α were significantly elevated in both models. However, administration of FGF21 significantly reduced these inflammatory cytokines. Real-time PCR and Western blot analysis showed that treatment with FGF21 significantly decreased mRNA and protein expressions of collagenI, α-SMA and TGF-β. Platelet-derived growth factor-BB (PDGF-BB) stimulant was used to establish the experimental cell model in hepatic stellate cells (HSCs). Real-time PCR and Western blot analysis demonstrated that the expression of collagenI and α-SMA were significantly upregulated by this stimulant in model group. Interestingly, our results showed that mRNA and protein expressions of leptin were also significantly induced in PDGF-BB treated HSCs. Administration of FGF21 significantly reduced leptin expression in a dose dependent manner and these effects were reversed in siRNA (against β-klotho) transfected HSCs. Furthermore, the leptin signaling pathways related protein p-ERK/t-ERK, p-STAT3/STAT3 and TGF-β were significantly downregulated by FGF21 treatment in a dose dependent manner. The expressions of SOCS3 and Nrf-2 were enhanced by treatment with FGF21. The underlying mechanism may be that FGF21 regulates leptin-STAT3 axis via Nrf-2 and SOCS3 pathway in activated HSCs.

Conclusions

FGF21 ameliorates hepatic fibrosis by multiple mechanisms.

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Data availability

The data analyzed during the current study may be available upon reasonable request.

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Funding

This study was supported by a grant from the major prophase project of Heilongjiang development and reform commission ([2011]1570), education department of Heilongjiang province (TSTAU-R2018017) and National Key R&D program of China (2017YFD0501102, 2017YFD0501103-03).

Author information

Authors and Affiliations

  1. Northeast Agricultural University, Harbin, China

    Fanrui Meng, Kai Kang, Qi He, Yukai Cao, Xinghao Jiang & Deshan Li

  2. Department of Biochemistry, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, Pakistan

    Mir Hassan Khoso

  3. Jiangsu Kanion Pharmaceutical CO. LTD, Jiangsu, Lianyungang, State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu, 220000, China

    Wei Xiao

Authors
  1. Fanrui Meng
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  2. Mir Hassan Khoso
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  3. Kai Kang
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  4. Qi He
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  5. Yukai Cao
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  6. Xinghao Jiang
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  7. Wei Xiao
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  8. Deshan Li
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Contributions

FRM performed the research, and analyzed the data. KMH, KK, QH, YKC and XHJ participated in data collection and analysis. WX and DSL contributed to the initial and consequent project discussion, manuscript discussion and revision. All the authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Wei Xiao or Deshan Li.

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Conflict of interest

The authors declare that there are no conflict of interest.

Ethical approval

This study was approved by the ethics committee of Northeast Agriculture University. All experimental protocols followed the guidelines issued by National Institute of Health and the Institutional Animal Care and Use Committee of Northeast Agriculture University. The mice were euthanatized under anesthesia induced by intraperitoneal injection of 1.2% avertin (Sigma, USA) at a dose of 20 μL/g body weight.

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Meng, F., Khoso, M.H., Kang, K. et al. FGF21 ameliorates hepatic fibrosis by multiple mechanisms. Mol Biol Rep 48, 7153–7163 (2021). https://doi.org/10.1007/s11033-021-06707-0

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