Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene. [5] It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders. [6] [7]
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This growth factor is a high affinity, heparin dependent ligand for FGFR4. [8] Expression of this gene was detected only in fetal but not adult brain tissue. [9] Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development. [5] [10] [11]
The orthologous protein in mouse is FGF15, which shares about 50% amino acid identity and has similar functions. Together they are often referred to as FGF15/19. [6] [7]
FGF19 has important roles as a hormone produced in the ileum in response to bile acid absorption. [7] Bile acids bind to the farnesoid X receptor (FXR), stimulating FGF19 transcription. Several FXR / bile acid response elements have been identified in the FGF19 gene. [12] Human FGF19 transcripts have been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including chenodeoxycholic acid, glycochenodeoxycholic acid and obeticholic acid in explants of ileal mucosa. [13]
FGF19 regulates new bile acid synthesis, acting through the FGFR4/Klotho-β receptor complexes in the liver to inhibit CYP7A1. [14] [15] [16] [17]
FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models. [18] [19] [20]
When FGF19 was inhibited by specific anti-FGF19 antibodies in monkeys, severe diarrhea was the result. There was also evidence of liver toxicity. Increases in bile acid synthesis, serum and fecal total bile acids, and specific bile acid transporters were found. [21]
FGF19 is frequently amplified in human cancers. [22] Amplification of the FGF19 genomic locus was found in liver cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, and esophageal cancer, among others. [23] [24] [25] [26] [27] Targeting FGF19 inhibits tumor growth in colon cancer cells and hepatocellar carcinoma. [28] [29] Increase in FGF19 correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. [30] [31] [32]
Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19. [33] Surgical resection of the ileum (as often occurs in Crohn's disease) will reduce bile acid absorption and remove the stimulus for FGF19 production.
In primary bile acid diarrhea, absorption of bile acids is usually normal, but defective FGF19 production can produce excessive bile acid synthesis, as shown by increased levels of 7α-hydroxy-4-cholesten-3-one, and excessive bile acid fecal loss, indicated by reduced SeHCAT retention. [33] [34] This was confirmed in a prospective study of patients with chronic diarrhea, where the predictive value for FGF19 in diagnosis of primary bile acid diarrhea and response to bile acid sequestrants was demonstrated. [35]
FGF19 is also found in the liver of patients with cholestasis. [36] It can be synthesised in the gall-bladder and secreted into bile. [37] FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis. [38]
Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19. [39] [40] FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass and other types of bariatric surgery. [41] [42]
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the FGF2 gene. It binds to and exerts effects via specific fibroblast growth factor receptor (FGFR) proteins, themselves a family of closely related molecules. Fibroblast growth factor protein was first purified in 1975; soon thereafter three variants were isolated: 'basic FGF' (FGF2); Heparin-binding growth factor-2; and Endothelial cell growth factor-2. Gene sequencing revealed that this group is the same FGF2 protein and is a member of a family of FGF proteins.
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.
Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1. Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.
The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.
Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 is a protein that in humans is encoded by the FGFR2 gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor.
Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.
Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location q16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.
Liver cancer is cancer that starts in the liver. Liver cancer can be primary or secondary. Liver metastasis is more common than that which starts in the liver. Liver cancer is increasing globally.
Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.
Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.
Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the FGF21 gene. Together with FGF19 and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth factor (FGF) family. FGF21 is a potent, extracellularly acting metabolic regulator, whose action was discovered through in vitro phenotypic screeninig and diet manipulation studies in rodents., unlike canonical growth-stimulating FGFs known to stimulate mitosis, differentiation and angiogenesis in their target tissues, FGF21 exerts its action by activating FGF21 receptors located in the cell membrane of target cells. Each FGF21 receptor is composed of a transmembrane FGF receptor protein, and its complexing co-receptor β-Klotho. Loss of β-Klotho abolishes all effects of FGF21 in vitro and in vivo. In addition to its action as a hormone, FGF21 may be able to act in an autocrine fashion, or possibly also in a paracrine manner in the pancreas.
Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lypophilic-masked analog of 5-FU that can be administered orally.
Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt diarrhea or bile salt malabsorption. It can result from malabsorption secondary to gastrointestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective.
7α-Hydroxy-4-cholesten-3-one is an intermediate in the biochemical synthesis of bile acids from cholesterol. Its precursor, 7α-hydroxycholesterol, is produced from cholesterol by hepatic cholesterol 7α-hydroxylase (CYP7A1).
Brivanib alaninate (INN/USAN) also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by Bristol-Myers Squibb for the treatment of hepatocellular carcinoma or HCC, the most common type of liver cancer. Brivanib is no longer in active development.
Fibroblast growth factor 15 is a protein in mouse encoded by the Fgf15 gene. It is a member of the fibroblast growth factor (FGF) family but, like FGF19, FGF21 and FGF23, has endocrine functions. FGF19 is the orthologous protein in humans. They are often referred together as FGF15/19.
FGF15/19 refers to two orthologous fibroblast growth factors which share 50% aminoacid identity and have similar functions. FGF15 was described in the mouse; FGF19 was found in humans and other species. They share physiological functions and so are often referred to as FGF15/19 or as FGF15/FGF19.
Erdafitinib, sold under the brand name Balversa, is an anti-cancer medication. It is a small molecule inhibitor of fibroblast growth factor receptor (FGFR) used for the treatment of cancer. FGFRs are a subset of tyrosine kinases which are unregulated in some tumors and influence tumor cell differentiation, proliferation, angiogenesis, and cell survival. Astex Pharmaceuticals discovered the drug and licensed it to Janssen Pharmaceuticals for further development.
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