Fgf15

Official Full Name

fibroblast growth factor 15

Organism

Mus musculus

GeneID

14170

Background

Predicted to enable fibroblast growth factor receptor binding activity and growth factor activity. Acts upstream of or within several processes, including negative regulation of bile acid biosynthetic process; neural crest cell migration; and response to bacterium. Predicted to be located in extracellular region. Predicted to be active in cytoplasm and extracellular space. Is expressed in several structures, including brain; branchial arch endoderm; embryo ectoderm; mesonephros; and sensory organ. Orthologous to human FGF19 (fibroblast growth factor 19). [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

Fgf15; FGF19; Fgf8a;

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Detailed Information

Enterohepatic fibroblast growth factor (FGF19) in humans and its corresponding counterpart Fgf15 in rodents work as a significant regulator in gut-liver signaling axis, for the biosynthesis of bile acid and glucose and lipid homeostasis of different physiological and pathological stages. For the combination between fibroblast growth factor (FGF) 15/19 and liver fibroblast growth factor receptor 4 (Fgfr4), liver becomes the target organ after secreting from the enterocyte into the portal circulation. Specificity of affinition between FGF15/19 and Fgfr4 is magnified by accumulative expression of single-pass transmembrane protein β-Klotho in liver tissue. Enterohepatic feed-back regulation of BA homeostasis is the teamwork of FGF15/19 and FGFR4, and FGFR4 works as receptor tyrosine kinase tailored for FGF15/19 in the liver, it is beneficial for BA synthesis rate-limiting for its down-regulation on cytochrome P450 isoform 7A1 (CYP7A1), while hepatic X receptor (FXR) activation induced BA synthesis inhibition via up-regulated small heterodimer partner (SHP) suppressing CYP7A1 expression independent of enterohepatic FGF15/19 signaling, thus inhibiting BA synthesis. BAs reabsorption is negatively feedback regulated by BAs in the ileum, in mice models, transcription of intestinal BA binding protein (Ibabp) and Fgf15 induced by BAs in the enterocyte affects the activation of FXR.

Murine Intestinal inflammation regulated by Fgf15-FXR axis and bile acid composition

Gut-liver axis comes to be the spotlight of recent research about intestinal and hepatic diseases, particularly inflammatory disease (IBD), which is affected by both organs. IBD occurrence has a significant correlation with cholestatic liver diseases such as primary sclerosing cholangitis (PSC). However, biomolecular level mechanisms have not been found to explain the strong associations between the two mentioned diseases. DSS induced colitis murine is widely-accepted IBD model, whose severity and pathological abnormity sites depend on several external factors, including quantity and molecular weight of DSS, duration of administrations, and the mouse strains. Typically, inflammation is constraint to large intestine or small bowel, and the interleukin 10 (IL10^(-/-)) knockout mice was developed as mature IBD models with a more pronounced and continuously increasing inflammation in the entire gastrointestinal tract including the ileum compared with wide types. In clinical observations, patients with UC showed slightly increased or rather unchanged FGF19 serum concentrations in comparison with healthy controls. There are increased serum FGF19 levels in DSS treated colitis model and decreased one in 10 (IL10^(-/-)) knockout mice, and it is consistent with the conditions in human patients.

FGF15 works as stimuli for Hippo signaling to inhibit BA metabolism and liver tumorigenesis

Even it is untouchable for external factors for regulating Hippo signaling pathway, Chen's group reported activation of Hippo signaling by FGF15 can inhibit BA metabolism and liver tumorigenesis. Secretion of FGF15 in ileal enterocyte is induced by FXR in response to increased volume of bile acid. Enterohepatic circulating FGF15 was found to be stimulative for hepatic receptor FGFR4 to recruit and phosphorylate NF2, and further switching FGFR4's role from pro-oncogenic to anti-tumor by alleviating inhibitory effect of Raf on the Hippo kinases Mst1/2. Activation of Mst 1/2 subsequent with phosphorylation and SHP stabilization can downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thus limiting bile acid synthesis. Conversely, the absence of Mst1/2 would damage bile acid metabolism and remarkably elevate Cyp7a1 expression. Depletion of intestinal bile acids retards Mst1/2-mutant-driven liver overgrowth and oncogenesis.

Fig 1. Mechanism of FGF15 echoed with bile acids in the enterohepatic cycle (M. Avila et al. 2018)

References:

Monika Rau, MD, Bruno Stieger. (2016) 'Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation', Inflamm Bowel Dis, doi: 10.1097/MIB.0000000000000879.
Suyuan Ji, Qingxu Liu, Shihao Zhang. (2018) 'FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis, Developmental Cell, 2019, doi: 10.1016/j.devcel.2018.12.021.
G. Álvarez‐Sola, Uriarte, M. Latasa, Maddalen Jiménez. (2018) 'Bile acids, FGF15/19 and liver regeneration: From mechanisms to clinical applications', Biochimica et biophysica acta, doi: 10.1016/j.bbadis.2017.06.025.

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