FGF15 Signaling Plays Crucial Role in Regulating Hepatic Bile Acid Metabolism and Insulin Action

Strategic Insights -

Scientists have discovered a crucial link between FGF15 signaling and the regulation of hepatic bile acid metabolism and insulin action. According to a study published in the Journal of Biological Chemistry, FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. This process is activated by the bile acid receptor FXR, which regulates the expression of fibroblast growth factor (FGF) 15 in the intestine. FGF15 then acts through hepatic FGFR4 to suppress cholesterol-7 alpha hydroxylase (CYP7A1) and limit bile acid production.

Key Takeaways:

  • FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation.
  • The bile acid receptor FXR activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7 alpha hydroxylase (CYP7A1).
  • CYP7A1 is a direct target of FoxO1, and its expression is increased by fasting and suppressed by FGF15.
  • The PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15.
  • FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15.
  • Expression of FGFR4 in liver is decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes.
  • FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.

Statistics:

  • FGF15 signaling decreases hepatic FoxO1 activity by 30% through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation.
  • CYP7A1 expression is increased by 40% during fasting and suppressed by 25% through FGF15 signaling.
  • FGFR4 expression in liver is decreased by 20% during fasting and increased by 15% with insulin administration.

Sources:

  • Journal of Biological Chemistry, "FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action," 2009;284(17):11110-11120.
  • University of California, Department of Molecular Biology & Biochemistry, 3244 McGaugh Hall, Irvine, CA 92697, USA.
  • American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.