Fgf15, the mouse ortholog of human FGF19, is a hormone secreted by ileal enterocytes. It plays a crucial role in the bile acid-FXR-FGF15/19 signaling axis. Bile acids activate the nuclear receptor farnesoid X receptor (FXR) in the ileum, which then regulates the production of Fgf15. Fgf15 travels via the enterohepatic circulation to the liver, where it activates the FGFR4-β-klotho receptor complex, regulating gene expression related to cholesterol, bile acid, and lipid metabolism [1,4].

Intestine-derived Fgf15-knockout (FGF15INT-KO) mice studies showed that gut-derived Fgf15 is important for regulating bile acid and cholesterol metabolism but not essential for energy and glucose balance. FGF15INT-KO mice had increased systemic bile acid levels and decreased cholesterol levels when exposed to an obesogenic diet [2]. Also, Fgf15-null mice did not develop cardiac hypertrophy in response to high-fat diet, isoproterenol, or cold exposure, indicating its role in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium [3].

In conclusion, Fgf15 is a key player in the regulation of bile acid, cholesterol, and fatty acid metabolism, as well as cardiac hypertrophy. Gene-knockout mouse models have been instrumental in revealing these functions, providing insights into its potential role in metabolic syndrome and heart-related disease conditions.

References:

1. Katafuchi, Takeshi, Makishima, Makoto. 2022. Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. In International journal of molecular sciences, 23, . doi:10.3390/ijms23116046. https://pubmed.ncbi.nlm.nih.gov/35682726/

2. Bozadjieva-Kramer, Nadejda, Shin, Jae Hoon, Li, Ziru, Rothberg, Amy E, Seeley, Randy J. 2024. Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance. In JCI insight, 9, . doi:10.1172/jci.insight.174164. https://pubmed.ncbi.nlm.nih.gov/38587078/

3. Morón-Ros, Samantha, Blasco-Roset, Albert, Navarro-Gascon, Artur, Gavaldà-Navarro, Aleix, Planavila, Anna. 2023. A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy. In The Journal of pathology, 261, 335-348. doi:10.1002/path.6193. https://pubmed.ncbi.nlm.nih.gov/37650293/

4. Kliewer, Steven A, Mangelsdorf, David J. 2015. Bile Acids as Hormones: The FXR-FGF15/19 Pathway. In Digestive diseases (Basel, Switzerland), 33, 327-31. doi:10.1159/000371670. https://pubmed.ncbi.nlm.nih.gov/26045265/