首页|FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
Immune-mediated liver injury(ILI)is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes.Fibroblast growth factor 4(FGF4)was recently identified as a hepatoprotective cytokine;however,its role in ILI remains unclear.In patients with auto-immune hepatitis(type of ILI)and mouse models of concanavalin A(ConA)-or S-100-induced ILI,we observed a biphasic pattern in hepatic FGF4 expression,characterized by an initial increase followed by a return to basal levels.Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway,aggravating hepatocellular apoptosis.This led to intrahepatic immune hyper-reactivity,inflammation accentuation,and subsequent liver injury in both ILI models.Conversely,administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance,thereby mitigating liver damage.The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4,which activated the Ca2+/calmodulin-dependent protein kinasekinase 2(CaMKKβ)and its downstream phos-phatase and tensin homologue-induced putative kinase 1(PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L(Bcl-XL)signalling axis in the mitochondria.Hence,FGF4 serves as an early response factor and plays a protective role against ILI,suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Fibroblast growth factor 4Fibroblast growth factor receptor 4Immune liver injuryCa2+/Calmodulin dependent protein kinase 2PTEN-induced putative kinase 1Mitochondria-associated apoptosis

Zhifeng Huang、Tongtong Pan、Liang Xu、Lu Shi、Xiong Ma、Liya Zhou、Luyao Wang、Jiaojiao Wang、Guoqing Zhu、Dazhi Chen、Lingtao Song、Xiaomin Pan、Xiaodong Wang、Xiaokun Li、Yongde Luo、Yongping Chen

展开 >

Hepatology Diagnosis and Treatment Center Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325035,China

Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health)& School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China

School of Laboratory Medicine and Life Sciences,Wenzhou Medical University & Key Laboratory of Laboratory Medicine,Ministry of Education,Wenzhou Medical University,Wenzhou 325035,China

Division of Gastroenterology and Hepatology,Key Laboratory of Gastroenterology and Hepatology,Ministry of Health,State Key Laboratory for Oncogenes and Related Genes,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200001,China

Hangzhou Medical College,Hangzhou 311300,China

展开 >

国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金浙江省自然科学基金重点项目浙江省自然科学基金重点项目Key Project from Science Technology Department of Wenzhou,China

82070593920571228022300382002965LD21H030002DQ24H310001ZY2021022

2024

10.1016/j.apsb.2023.12.012

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(4)
  • 51