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FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury

Author

Listed:
  • Xinyu Yang

    (Hangzhou First People’s Hospital
    Zhejiang University School of Medicine)

  • Hao Chen

    (Zhejiang University School of Medicine)

  • Wei Shen

    (Zhejiang University School of Medicine)

  • Yuanming Chen

    (Zhejiang University School of Medicine)

  • Zuyuan Lin

    (Hangzhou First People’s Hospital
    Zhejiang University School of Medicine)

  • Jianyong Zhuo

    (Hangzhou First People’s Hospital)

  • Shuai Wang

    (Hangzhou First People’s Hospital)

  • Modan Yang

    (Zhejiang University School of Medicine)

  • Huigang Li

    (Zhejiang University School of Medicine)

  • Chiyu He

    (Zhejiang University School of Medicine)

  • Xuanyu Zhang

    (Zhejiang University School of Medicine)

  • Zhihang Hu

    (Zhejiang University School of Medicine)

  • Zhengxing Lian

    (Hangzhou First People’s Hospital)

  • Mengfan Yang

    (Qilu Hospital of Shandong University)

  • Rui Wang

    (Zhejiang University Medical Center)

  • Changbiao Li

    (Hangzhou Medical College)

  • Binhua Pan

    (Hangzhou First People’s Hospital)

  • Li Xu

    (Zhejiang University School of Medicine)

  • Jun Chen

    (Hangzhou Medical College)

  • Xuyong Wei

    (Hangzhou First People’s Hospital)

  • Qiang Wei

    (Hangzhou Medical College)

  • Haiyang Xie

    (NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Shusen Zheng

    (Zhejiang University School of Medicine
    NHC Key Laboratory of Combined Multi-organ Transplantation
    Shulan (Hangzhou) Hospital)

  • Di Lu

    (Hangzhou Medical College
    NHC Key Laboratory of Combined Multi-organ Transplantation)

  • Xiao Xu

    (Hangzhou Medical College
    NHC Key Laboratory of Combined Multi-organ Transplantation
    Zhejiang University)

Abstract

Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT.

Suggested Citation

  • Xinyu Yang & Hao Chen & Wei Shen & Yuanming Chen & Zuyuan Lin & Jianyong Zhuo & Shuai Wang & Modan Yang & Huigang Li & Chiyu He & Xuanyu Zhang & Zhihang Hu & Zhengxing Lian & Mengfan Yang & Rui Wang &, 2024. "FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52379-2
    DOI: 10.1038/s41467-024-52379-2
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