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FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action

Dong-Ju Shin1, Timothy F Osborne

  • 1Department of Molecular Biology and Biochemistry, School of Biological Sciences and Center for Diabetes Research and Treatment, University of California, Irvine, California 92697-3900, USA.

The Journal of Biological Chemistry
|February 25, 2009
PubMed

Insights

Fibroblast growth factor 15 (FGF15) signaling suppresses bile acid production by inhibiting forkhead transcription factor 1 (FoxO1) activity. This pathway integrates insulin and FGF signaling to regulate glucose and bile acid metabolism.

Area of Science:

  • Metabolic regulation
  • Hepatology
  • Endocrinology

Background:

  • Fibroblast growth factor 15 (FGF15) signaling, activated by the bile acid receptor FXR, suppresses bile acid production via hepatic FGFR4.
  • Forkhead transcription factor 1 (FoxO1) activity and cholesterol-7alpha hydroxylase (CYP7A1) gene expression increase during fasting.
  • CYP7A1 is a key enzyme in bile acid synthesis.

Purpose of the Study:

  • To investigate if CYP7A1 is a direct target gene of FoxO1.
  • To elucidate the role of the PI 3-kinase pathway in CYP7A1 regulation by fasting and FGF15.
  • To determine the role of FGFR4 in hepatic FGF15 signaling and its regulation by insulin.

Main Methods:

  • Western blotting to assess protein phosphorylation.
  • Quantitative PCR to measure gene expression.
  • Animal models of fasting and diabetes.

Main Results:

  • CYP7A1 was confirmed as a direct target of FoxO1.
  • The PI 3-kinase pathway is crucial for both fasting-induced CYP7A1 expression and FGF15-mediated suppression.
  • Hepatic FGFR4 expression is regulated by fasting and insulin, and is the primary receptor for FGF15's hepatic effects.
  • FGFR4 expression decreased with fasting, increased with insulin, and reduced in diabetes.

Conclusions:

  • FoxO1 integrates FGF and insulin signaling pathways.
  • This integration is critical for regulating both glucose and bile acid metabolism.
  • FGFR4 is a key target of insulin regulation in the liver.

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