FGF-19

The FGFs are a family of more than 20 small (~17–26 kDa) secreted peptides. The initial characterization of these proteins focused on their ability to stimulate fibroblast proliferation. This mitogenic activity was mediated through FGF receptors (FGFRs) 1, 2, or 3. A fourth closely related tyrosine kinase receptor (FGFR4) was able to bind the FGFs but did not lead to a mitogenic response. FGFs modulate cellular activity via at least 5 distinct subfamilies of high-affinity FGF receptors (FGFRs): FGFR-1, -2, -3, and -4, all with intrinsic tyrosine kinase activity and, except for FGFR-4, multiple splice isoforms, and FGFR-5, which lacks an intracellular kinase domain. There is growing evidence that FGFRs can be important for regulation of glucose and lipid homeostasis. The overexpression of a dominant negative form of FGFR-1 in β cells leads to diabetes in mice, which thus implies that proper FGF signaling is required for normal β cell function and glycemia maintenance. FGFR-2 appears to be a key molecule during pancreatic development. Moreover, FGFR-4 has been implicated in cholesterol metabolism and bile acid synthesis. FGF-19, has been shown to cause resistance to diet-induced obesity and insulin desensitization and to improve insulin, glucose, and lipid profiles in diabetic rodents. Since these effects, at least in part, are mediated through the observed changes in metabolic rates, FGF-19 can be considered as a regulator of energy expenditure. FGF-21 is preferentially expressed in liver, but an exact knowledge of FGF-21 bioactivity and its mode of action have been lacking to date. FGF-21 is a potent activator of glucose uptake on adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and lowers blood glucose and triglyceride levels when therapeutically administered to diabetic rodents.

Image: FGF-19 protein structure and sequence

References:

1. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007 May;27(9):3417-28
2. Biliary secretion and excretion in health and disease: current concepts. Ann Hepatol 2007 Jan-Mar;6(1):15-27
3. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006 Dec;260(6):530-6
4. Effects of fibroblast growth factors 19 and 20 on cell multiplication and locomotion in a human embryonal carcinoma cell line (Tera-2) in vitro. Anticancer Res 2006 Sep-Oct;26(5A):3307-10
5. A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. J Lipid Res 2006 Feb;47(2):384-92
6. Expression of Fibroblast growth factor 19 (Fgf19) during chicken embryogenesis and eye development, compared with Fgf15 expression in the mouse. Gene Expr Patterns 2004 Oct;4(6):687-93