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FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice

Author

Listed:
  • Gaozan Tong

    (Wenzhou Medical University
    Wenzhou Medical University)

  • Yiming Chen

    (The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University)

  • Xixi Chen

    (Taizhou Central Hospital)

  • Junfu Fan

    (Wenzhou Medical University)

  • Kunxuan Zhu

    (Wenzhou Medical University)

  • ZiJing Hu

    (Wenzhou Medical University)

  • Santie Li

    (Wenzhou Medical University)

  • Junjie Zhu

    (Wenzhou Medical University)

  • Jianjun Feng

    (Wenzhou Medical University)

  • Zhaohang Wu

    (Wenzhou Medical University)

  • Zhenyu Hu

    (Wenzhou Medical University)

  • Bin Zhou

    (Wenzhou Medical University)

  • Litai Jin

    (Wenzhou Medical University)

  • Hui Chen

    (Wenzhou Medical University)

  • Jingling Shen

    (Wenzhou University)

  • Weitao Cong

    (Wenzhou Medical University
    Wenzhou Medical University
    Wenzhou Medical University)

  • XiaoKun Li

    (Wenzhou Medical University
    Wenzhou Medical University)

Abstract

Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.

Suggested Citation

  • Gaozan Tong & Yiming Chen & Xixi Chen & Junfu Fan & Kunxuan Zhu & ZiJing Hu & Santie Li & Junjie Zhu & Jianjun Feng & Zhaohang Wu & Zhenyu Hu & Bin Zhou & Litai Jin & Hui Chen & Jingling Shen & Weitao, 2023. "FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41800-x
    DOI: 10.1038/s41467-023-41800-x
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    1. Eri H. Kobayashi & Takafumi Suzuki & Ryo Funayama & Takeshi Nagashima & Makiko Hayashi & Hiroki Sekine & Nobuyuki Tanaka & Takashi Moriguchi & Hozumi Motohashi & Keiko Nakayama & Masayuki Yamamoto, 2016. "Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    2. Wei Yang & Yun-Hwa Lee & Amanda E. Jones & Jessica L. Woolnough & Dewang Zhou & Qian Dai & Qiang Wu & Keith E. Giles & Tim M. Townes & Hengbin Wang, 2014. "The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment," Nature Communications, Nature, vol. 5(1), pages 1-15, September.
    3. Maddalena Adorno & Shaheen Sikandar & Siddhartha S. Mitra & Angera Kuo & Benedetta Nicolis di Robilant & Veronica Haro-Acosta & Youcef Ouadah & Marco Quarta & Jacqueline Rodriguez & Dalong Qian & Vadi, 2013. "Usp16 contributes to somatic stem-cell defects in Down’s syndrome," Nature, Nature, vol. 501(7467), pages 380-384, September.
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