Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Abstract

Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15–/– mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15–/– mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4‐induced LF model in wild type (WT), Fgf15–/–, and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine‐ or cholic acid–containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15–/– mice; and (3) treatment of a human HSC line, LX‐2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15–/– mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15–/– mice. HSCs from Fgf15–/– mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX‐2 cells, FXR activation increased peroxisome proliferator‐activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c‐Jun N‐terminal kinase pathways and reduced nuclear factor kappa‐light‐chain‐enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

miR-7-5p Promotes Hepatic Stellate Cell Activation by Targeting Fibroblast Growth Factor Receptor 4

“…Many of FGF19 targets are related to metabolism and proliferation [23]. Several experiments have demonstrated that FGF19 exerts a protective effect against liver fibrosis [24][25][26][27]. Binding to FGFR4 is required for FGF19 proliferative function in mouse livers [28,29].…”

Retinal inputs signal astrocytes to recruit interneurons into visual thalamus

“…The ability of FGFs to influence cell migration, the expression of Fgf15 along a potential migratory path of interneurons, and the regulation of Fgf15 expression by retinal input led us to hypothesize that FGF15 may be necessary for the recruitment of GABAergic interneurons into the neonatal visual thalamus. To test this, we employed Fgf15 −/− mutant mice, which lack functional FGF15, by deleting the entire third exon of the gene, which encodes for half of the protein, including the FGFRand heparin-binding motifs (50,51). While a significant fraction of Fgf15 −/− mutant mice die embryonically, some survive into adulthood (50,52).…”

Bile Acids and FXR: Novel Targets for Liver Diseases

“…Activation of FXR induces SHP to increase the peroxisomal proliferator-activated receptor γ (PPARγ) expression in HSCs, and PPARγ is well-known to inactivate HSCs (71,72). Recently, we have shown that FGF15 deficiency reduces hepatic fibrosis through increasing FXR activation following loss of FGF15-mediated suppression of BA synthesis (73,74). Interestingly, in a human HSC cell line, LX2, FGF19 does not suppress fibrogenic gene expression, but suppresses inflammation, likely through modulating the inhibitor of nuclear factor kappa B (IκB) activity (74).…”

“…Recently, we have shown that FGF15 deficiency reduces hepatic fibrosis through increasing FXR activation following loss of FGF15-mediated suppression of BA synthesis (73,74). Interestingly, in a human HSC cell line, LX2, FGF19 does not suppress fibrogenic gene expression, but suppresses inflammation, likely through modulating the inhibitor of nuclear factor kappa B (IκB) activity (74). These studies provide another group of evidence to support the role of FXR as a homeostatic regulator to suppress liver inflammation and fibrosis.…”