FGF19

Fibroblast growth factor 19 is a is_associated_with::protein that in humans is encoded by the FGF19 is_associated_with::gene. It functions as a is_associated_with::hormone, regulating is_associated_with::bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic is_associated_with::bile acid diarrhea and in certain metabolic disorders.

Functions
The protein encoded by this gene is a member of the is_associated_with::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, is_associated_with::morphogenesis, tissue repair, tumor growth and invasion. This growth factor is a high affinity, is_associated_with::heparin dependent ligand for is_associated_with::FGFR4. Expression of this gene was detected only in fetal but not adult brain tissue. Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development.

The orthologous protein in mouse is is_associated_with::FGF15, which shares about 50% amino acid identity and has similar functions. Together they are often referred to as is_associated_with::FGF15/19.

FGF19 has important roles as a hormone produced in the is_associated_with::ileum in response to is_associated_with::bile acid absorption. Bile acids bind to the is_associated_with::farnesoid X receptor (FXR), stimulating FGF19 transcription. Several FXR / bile acid response elements have been identified in the FGF19 gene. Human FGF19 transcripts have been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including is_associated_with::chenodeoxycholic acid, is_associated_with::glycochenodeoxycholic acid and is_associated_with::obeticholic acid in explants of ileal mucosa.

FGF19 regulates new is_associated_with::bile acid synthesis, acting through the is_associated_with::FGFR4/Klotho-β receptor complexes in the liver to inhibit is_associated_with::CYP7A1.

FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models.

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.

Clinical significance
Patients with is_associated_with::chronic diarrhea due to is_associated_with::bile acid malabsorption have been shown to have reduced fasting FGF19. Surgical resection of the ileum (as often occurs in is_associated_with::Crohn's disease) will reduce bile acid absorption and remove the stimulus for FGF19 production.

In is_associated_with::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 is_associated_with::7α-hydroxy-4-cholesten-3-one, and excessive bile acid fecal loss, indicated by reduced is_associated_with::SeHCAT retention. 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 is_associated_with::bile acid sequestrants was demonstrated.

FGF19 is also found in the liver of patients with is_associated_with::cholestasis. It can be synthesised in the gall-bladder and secreted into bile. FGF19 is expressed in around half of is_associated_with::hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.

Patients with the is_associated_with::metabolic syndrome, is_associated_with::non-alcoholic fatty liver disease and is_associated_with::insulin resistance have reduced levels of FGF19. FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass is_associated_with::bariatric surgery.