FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury
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.
Authors
- Yuanming Chen (ORCID: https://orcid.org/0000-0001-7955-3350)
- Xuanyu Zhang (ORCID: https://orcid.org/0009-0000-9240-7956)
- Huigang Li (ORCID: https://orcid.org/0000-0002-5575-8068)
- Xiao Xu (ORCID: https://orcid.org/0000-0002-2761-2811)
- Modan Yang (ORCID: https://orcid.org/0009-0005-4983-2224)
- Xu Li (ORCID: https://orcid.org/0000-0003-0684-6923)
- Zuyuan Lin
- Mengfan Yang
- Chiyu He (ORCID: https://orcid.org/0000-0002-1794-2876)
- Xinyu Yang (ORCID: https://orcid.org/0000-0002-5248-2051)
- Changbiao Li (ORCID: https://orcid.org/0000-0002-5319-3251)
- Xuyong Wei (ORCID: https://orcid.org/0000-0001-8755-5268)
- Zhengxing Lian (ORCID: https://orcid.org/0000-0001-8418-4916)
- Jianyong Zhuo
- Shuai Wang (ORCID: https://orcid.org/0000-0002-9252-7496)
- Hao Chen (ORCID: https://orcid.org/0000-0003-4339-3441)
- Haiyang Xie (ORCID: https://orcid.org/0000-0002-6913-9284)
- Rui Wang (ORCID: https://orcid.org/0009-0009-7636-1586)
- Shusen Zheng (ORCID: https://orcid.org/0000-0003-1459-8261)
- Wei Shen (ORCID: https://orcid.org/0000-0001-9040-070X)
- Qiang Wei (ORCID: https://orcid.org/0000-0003-1935-520X)
- Di Lu (ORCID: https://orcid.org/0000-0002-8724-3739)
- Binhua Pan
- Jun Chen
- Zhihang Hu
Institutions
- Zhejiang Chinese Medical University (CN)
- Zhejiang Provincial People's Hospital (CN)
- Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN)
- Hangzhou Red Cross Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- Qilu Hospital of Shandong University (CN)
- Ministry of Public Health (MG)
- Hangzhou Medical College (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1038/s41467-024-52379-2
- Citations
- 22
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 5.14