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.

SUBMITTER: Schumacher JD 

PROVIDER: S-EPMC6918008 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature