糖皮质激素通过FGF6-FGFBP1轴引发肌肉-肝脏串扰，以减轻急性肝损伤并促进肝脏再生。

Glucocorticoids trigger muscle-liver crosstalk to attenuate acute liver injury and promote liver regeneration via the FGF6-FGFBP1 axis.

作者信息

Xu Yue-Jie, Liu Cai-Zhi, Chen Ying, Li Lan-Xin, Xu Bo, You Ling-Xin, Meng Mei-Yao, Li Xin, Zhang Hong, Ding Qiu-Rong, Zhang Rong, Ma Xin-Ran, Chen Xiao-Hua, Hu Cheng

机构信息

Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.

Jinzhou Medical University Graduate Training Base (Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine), Jinzhou, 121001, Liaoning, China.

出版信息

Mil Med Res. 2025 Jul 21;12(1):36. doi: 10.1186/s40779-025-00618-y.

DOI:10.1186/s40779-025-00618-y

PMID:40685360

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12278513/

Abstract

BACKGROUND

Acute 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.

METHODS

Partial (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.

RESULTS

Integrated 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.

CONCLUSION

Our 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.

摘要

背景

急性肝损伤（ALI）需要快速的肝脏再生以避免致命的肝衰竭。作为关键机制，全身代谢重塑和器官间串扰对于这一再生过程至关重要。骨骼肌作为主要的代谢器官系统，在ALI期间会发生显著重塑。然而，其具体的调节作用在很大程度上仍未明确。

方法

采用部分（2/3）肝切除术和对乙酰氨基酚诱导雄性小鼠发生ALI。进行RNA测序（RNA-seq）、转座酶可及染色质测序分析（ATAC-seq）、染色质免疫沉淀、荧光素酶测定、蛋白质免疫印迹、TUNEL测定、免疫组织化学和相分离测定，以揭示其中涉及的转录轴。通过酶联免疫吸附测定评估ALI患者血清中成纤维细胞生长因子结合蛋白1（FGFBP1）的蛋白水平。

结果

对ALI后的RNA-seq和ATAC-seq进行综合分析，确定了糖皮质激素（GC）信号介导的对骨骼肌代谢中纤维母细胞生长因子6（FGF6）的调控。肌肉特异性敲低糖皮质激素受体（GR）会加重ALI并抑制肝脏再生。Fgf6基因敲除小鼠的ALI得到改善，肝脏再生增强，肌肉内注射FGF6中和抗体可挽救GR敲低诱导的有害作用。对FGF6下游靶点的进一步分析表明，FGF6通过细胞外信号调节激酶激活转录因子3信号传导来调节FGFBP1的表达。此外，FGF6通过干扰其在质膜上由液-液相分离（LLPS）驱动的凝聚物动力学来调节FGFBP1的肝素依赖性释放动力学。循环中的FGFBP1随后通过LLPS机制与肝成纤维细胞生长因子5（FGF5）相互作用，以调节肝脏再生。