Fibroblast growth factor 19

Fibroblast growth factor (FGF) 19 is an atypical member of the fibroblast growth factor family of signaling molecules. FGF19, FGF21, and FGF23 comprise a phylogenetic subfamily with attributes that distinguish them from typical FGFs. The FGF19 subfamily has reduced heparin binding resulting from a disrupted beta-trefoil domain. Reduced heparin binding allows these FGFs to diffuse beyond their site of origin and act as endocrine hormones. FGF19 is the only FGF to not have a closely related mouse homologue. The mouse homologue of FGF19, called FGF15, is only 53% identical to the human FGF19. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin.

Fibroblast growth factor 19 regulation

This family of FGFs is regulated, at least in part, by nuclear hormone receptors. FGF19 expression is regulated by the farnesoid X receptor, a nuclear hormone receptor that is a key regulator of bile acid biosynthesis and transport. In line with its regulation by a bile acid receptor, FGF19 is involved in the regulation of bile acid biosynthesis and gallbladder filling. FGF19 originates from intestine and signals to liver via the portal circulation with a pronounced diurnal pattern. Litocholic and chenodeoxycholic acid strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. The lithocholic acid responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with Litocholic acid or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells.

The transintestinal flux of bile acids regulates serum levels of intestinal fibroblast growth factor 19 that in turn modulate bile production in human liver.

Fibroblast growth factor 19 action

In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.

Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased paraoxonase 1 (PON1) mRNA levels. Deletion studies revealed that the proximal –230 to –96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.

Formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle was observed and an anti- FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4 abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

Fibroblast growth factor 19 in circulation

Basal FGF19 levels varied by 10-fold in normal subjects, and were reduced following treatment with a bile acids-binding resin and increased upon feeding chenodeoxycholic acid. Serum FGF19 levels exhibited a pronounced diurnal rhythm with peaks occurring 90–120 min after the postprandial rise in serum bile acids. The FGF19 peaks in turn preceded the declining phase of bile acid synthesis. The diurnal rhythm of serum FGF19 was abolished upon fasting.

Catalog Number	Species	Analyte	Assay	Regulatory	Format
RD191107200R	Human	Fibroblast Growth Factor 19	Sandwich ELISA, Biotin-labelled antibody	RUO	96 wells (1 kit)