| Glucocorticoids trigger muscle-liver crosstalk to attenuate acute liver injury and promote liver regeneration via the FGF6-FGFBP1 axis |
| 論文作者 |
Xu, YJ; Liu, CZ; Chen, Y; Li, LX; Xu, B; You, LX; Meng, MY; Li, X; Zhang, H; Ding, QR; Zhang, R; Ma, XR; Chen, XH; Hu, C |
| 期刊/會議名稱 |
MILITARY MEDICAL RESEARCH |
| 論文年度 |
2025 |
| 論文類別 |
|
| 摘要 |
BackgroundAcute liver injury (ALI) requires rapid hepatic regeneration to avert fatal liver failure. As key mechanisms, systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process. Skeletal muscle, as a major metabolic organ system, undergoes significant remodeling during ALI. However, its specific regulatory contributions remain largely uncharacterized.MethodsPartial (2/3) hepatectomy and acetaminophen were used to induce ALI in male mice. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin by sequencing (ATAC-seq), chromatin immunoprecipitation, luciferase assay, Western blotting, TUNEL assay, immunohistochemistry, and phase separation assays were performed to reveal the transcriptional axis involved. Serum fibroblast growth factor binding protein 1 (FGFBP1) protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.ResultsIntegrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid (GC) signaling-mediated regulation of fibroblast growth factor 6 (FGF6) in skeletal muscle metabolism. Muscle-specific knockdown of GC receptor (GR) exacerbates ALI and suppresses liver regeneration. Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration, with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown. Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling. Moreover, FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation (LLPS)-driven condensate dynamics at the plasma membrane. Circulating FGFBP1 subsequently interacts with hepatic fibroblast growth factor 5 (FGF5) through LLPS mechanisms to regulate liver regeneration.ConclusionOur results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis, providing a potential therapeutic target and treatment strategy for ALI. |
| 卷 |
12 |
| 影響因子 |
22.9 |
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