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 hepatop...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.展开更多
Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health prob...Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health problems in the world.Studies have shown that paracrine fibroblast growth factors(FGFs)play an important role in the occurrence and development of MAFLD by regulating glucose and lipid metabolism,inflammation,and fibrosis.This article reviews the latest progress in understanding of the distribution,function,and metabolic regulation of paracrine FGFs,which paves the way for future FGF-based therapies targeting MAFLD.展开更多
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).
文摘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.
基金This work was supported by the National Natural Science Foundation of China(Grant number 82070593)。
文摘Metabolic-dysfunction-associated fatty liver disease(MAFLD)is a group of highly heterogeneous multi-system diseases,which is closely related to metabolic dysfunction and is one of the most important public health problems in the world.Studies have shown that paracrine fibroblast growth factors(FGFs)play an important role in the occurrence and development of MAFLD by regulating glucose and lipid metabolism,inflammation,and fibrosis.This article reviews the latest progress in understanding of the distribution,function,and metabolic regulation of paracrine FGFs,which paves the way for future FGF-based therapies targeting MAFLD.
