FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523004811 |
| _version_ | 1797248340780384256 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhifeng Huang |
| collection | DOAJ |
| description | 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 Ca2+/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. |
| first_indexed | 2024-04-24T20:13:02Z |
| format | Article |
| id | doaj.art-5756349c51df4eb880a69f903e1fcdd2 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-24T20:13:02Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-5756349c51df4eb880a69f903e1fcdd22024-03-23T06:24:04ZengElsevierActa Pharmaceutica Sinica B2211-38352024-04-0114416051623FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosisZhifeng Huang0Tongtong Pan1Liang Xu2Lu Shi3Xiong Ma4Liya Zhou5Luyao Wang6Jiaojiao Wang7Guoqing Zhu8Dazhi Chen9Lingtao Song10Xiaomin Pan11Xiaodong Wang12Xiaokun Li13Yongde Luo14Yongping Chen15Hepatology 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; Corresponding authors.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; Corresponding authors.School of Laboratory Medicine and Life Sciences, Wenzhou Medical University & Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, Wenzhou 325035, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaDivision 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, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaHepatology 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, ChinaHepatology 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, ChinaHangzhou Medical College, Hangzhou 311300, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaHepatology 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, ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, ChinaHepatology 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, ChinaHepatology 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; Corresponding authors.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 Ca2+/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.http://www.sciencedirect.com/science/article/pii/S2211383523004811Fibroblast growth factor 4Fibroblast growth factor receptor 4Immune liver injuryCa2+/Calmodulin dependent protein kinase 2PTEN-induced putative kinase 1Mitochondria-associated apoptosis |
| spellingShingle | 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 FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis Acta Pharmaceutica Sinica B Fibroblast growth factor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca2+/Calmodulin dependent protein kinase 2 PTEN-induced putative kinase 1 Mitochondria-associated apoptosis |
| title | FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis |
| title_full | FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis |
| title_fullStr | FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis |
| title_full_unstemmed | FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis |
| title_short | FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis |
| title_sort | fgf4 protects the liver from immune mediated injury by activating camkkβ pink1 signal pathway to inhibit hepatocellular apoptosis |
| topic | Fibroblast growth factor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca2+/Calmodulin dependent protein kinase 2 PTEN-induced putative kinase 1 Mitochondria-associated apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523004811 |
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