The role of fibroblast growth factor 15/19 (fgf15/19) in regulating circadian energy metabolism and liver tumorigenesis
Creators: name: Yang, Zhenning
Publisher: name: No Publisher Supplied
Year: 2025

description: Endocrine fibroblast growth factor 15/19 (mouse FGF15, human FGF19) functions as a crucial regulator of bile acid (BA) synthesis, lipid and glucose metabolism, and hepatocellular proliferation. Ileum-derived FGF15/19 is induced by the nuclear receptor Farnesoid X receptor (FXR) that is activated by increased BAs postprandially. Released FGF15/19 travels to the liver via portal venous circulation and binds to FGF receptor 4 (FGFR4) and co-receptor β-Klotho in hepatocytes to mediate relevant intracellular pathways, leading to the suppression of BA synthesis and gluconeogenesis, and enhancement of protein and glycogen synthesis in the liver. Recent investigations have shown that various mutations including missense mutation, gain-of-function, and loss-of-function mutations in Fgf15/FGF19 gene are associated with the onset, development and progression of hepatic metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). These findings suggest that enhancement of endocrine FGF15/19 signaling may potentially provide therapeutic strategies for MASLD and MASH prevention and/or treatment. Accumulating evidence indicates that chronic disruption of circadian rhythms caused by shift work, jet lag, or light--at-night (LAN) is associated with an increased risk of metabolic diseases and cancers in animal models and humans. Restoring and enhancing circadian homeostasis can help regulate metabolic processes such as glucose, BA and lipid metabolism, thereby preventing against metabolic disease development. Therefore, it is important to investigate the potential signaling pathways that connect circadian rhythms with energy metabolism, which may influence the disease onset and development. Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is one of the most common causes of cancer death worldwide. The most important and severe liver-related complication in MASH is the development of HCC. It is well established that FXR deficiency leads to spontaneous HCC in Fxr knockout (KO) mice. FXR can prevent HCC development in both BA-dependent and -independent pathways, and FGF15 is also involved in regulating a variety of liver functions. Thus, it is important to investigate the role of FGF15 in HCC initiation and promotion induced by FXR deficiency. The present studies demonstrated the disruption of central (melatonin and cortisol) and peripheral (clock genes (CGs) and clock-controlled genes (CCGs), nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) signaling, and FGF15-BA signaling) clock markers in night shift (NS) versus day shift (DS) nurses. The results findings indicate that desynchrony of circadian internal network and misalignment with external lighting and behavioral activity (rest/active and fasting/eating) schedules among shift workers contributes to metabolic dysregulation and increases the risk for metabolic diseases and cancers. In addition, FGF15/19 may be able to restore circadian expressions of genes involved in circadian rhythms and BA and lipid metabolism through the increase of NAD+-dependent SIRT1 signaling, leading to prevention against liver metabolic diseases associated with circadian disruption of energy metabolism. Lastly, our studies found that FGF15 overexpression prevented spontanoues HCC development caused by FXR deficiency. Both lower BA levels and reduced growth signaling pathways that are consequences of FGF15 overexpression maybe responsible for the reduced HCC carcinogenesis.