Disease relevance of FGF19

• These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas [1].
• Together with cardiac outflow tract defects in Fgf15 mutants, the conservation of enhancers in the hindbrain/spinal cord and pharyngeal epithelia suggests that human FGF19 (ortholog of Fgf15) is involved in early development and the distribution of cardiac neural crest cells and is one of the candidate genes for congenital heart defects [2].
• FGF-19 message is expressed in several tissues including fetal cartilage, skin, and retina, as well as adult gall bladder and is overexpressed in a colon adenocarcinoma cell line [3].
• BACKGROUND: The effects of two recently discovered heparin binding growth factors, FGF-19 and FGF-20, on the human embryonal carcinoma derived cell line Tera 2 were examined [4].

High impact information on FGF19

• Through the FGFR4 tyrosine kinase, FGF19 promotes MAPK phosphorylation in the developing and mature cornea [5].
• FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells in cell culture and in zebrafish embryos [5].
• Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein [1].
• In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle [1].
• We show here that mouse Fgf15 is the sequence homolog of chick and human Fgf19/FGF19 [6].

Biological context of FGF19

• Here, we report that FGF19 transgenic mice had a significant and specific reduction in fat mass that resulted from an increase in energy expenditure [7].
• The diurnal rhythm of serum FGF19 was abolished upon fasting [8].
• Through its systemic effects, circulating FGF19 may also mediate other known BA-dependent effects on lipid and carbohydrate metabolism [8].
• We proposed in 2002 the hypothesis that mouse Fgf15 might be the ortholog of human FGF19 based on comparative genomics [9].
• In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue [10].

Anatomical context of FGF19

• A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice [1].
• We have identified a novel fibroblast growth factor, FGF-19, the most distant member of the FGF family described to date [3].

Associations of FGF19 with chemical compounds

• The FGF19 transgenic mice had increased brown adipose tissue mass and decreased liver expression of acetyl coenzyme A carboxylase 2, providing two mechanisms by which FGF19 may increase energy expenditure [7].
• Basal FGF19 levels varied by 10-fold in normal subjects, and were reduced following treatment with a BA-binding resin and increased upon feeding the BA chenodeoxycholic acid [8].
• 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 [11].
• In all of the mice studied, dietary taurocholate increased ileal expression of FGF15, a FXR-inducible murine homologue of human FGF19 [12].
• The inhibitory effect of FGF-19 on insulin activation of hepatic fatty acid synthesis constitutes a mechanism that would explain the beneficial effect of FGF-19 on metabolic syndrome [13].

Physical interactions of FGF19

• The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4 [7].

Other interactions of FGF19

• The molecular behavior of FGF23 as a systemic factor can be justified by the altered conformation of the beta-trefoil structure similar to that suspected in FGF19 [14].
• The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone [11].
• FGF19 is a target for FOXC1 regulation in ciliary body-derived cells [5].
• Whereas FGF-20 promoted cell multiplication at low doses, FGF-19 was required at high doses to achieve a comparable effect [4].

References