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

作　　者：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 

机构地区：[1]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 [2]Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health)&School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China [3]School of Laboratory Medicine and Life Sciences,Wenzhou Medical University&Key Laboratory of Laboratory Medicine,Ministry of Education,Wenzhou Medical University,Wenzhou 325035,China [4]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 [5]Hangzhou Medical College,Hangzhou 311300,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第4期1605-1623,共19页药学学报（英文版）

基　　金：We appreciate the financial support from the National Natural Science Foundation of China(82070593,92057122,80223003,82002965 to Yongping Chen,Zhifeng Huang,Xiaokun Li,and Lintao Song);Key Project of Zhejiang Provincial Natural Science Foundation(LD21H030002,DQ24H310001 to Yongping Chen and Zhifeng Huang,China);Key Project from Science Technology Department of Wenzhou(ZY2021022 to Zhifeng Huang,China).

摘　　要：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 autoimmune 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 Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase 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.

关 键 词：Fibroblast growthfactor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca^(2+)/Calmodulin dependent protein 

分 类 号：R965[医药卫生—药理学]