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Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action

Jun Zhang1, Jamila Gupte1, Yan Gong1

  • 1Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.

Ebiomedicine
|January 3, 2017
PubMed

Insights

Fibroblast growth factor (FGF) 21 influences bile acid metabolism by increasing liver bile acid production and colon transit. This occurs by FGF21 antagonizing FGF15/19 signaling, revealing a new role for FGF21.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Hepatology

Background:

  • Fibroblast growth factor (FGF) 21 is known to regulate glucose, lipid, and energy homeostasis.
  • FGF21 shows therapeutic potential in obese humans with type 2 diabetes.
  • The role of FGF21 in bile acid metabolism has not been previously investigated.

Purpose of the Study:

  • To investigate the effect of fibroblast growth factor (FGF) 21 on bile acid metabolism.
  • To elucidate the underlying mechanism of FGF21-mediated changes in bile acid regulation.

Main Methods:

  • Adeno-associated virus (AAV)-mediated FGF21 overexpression in mice.
  • Analysis of bile acid pool size and liver enzyme expression (Cyp7a1).
  • Studies in cholecystectomized mice to assess bile acid transit.
  • Investigation of FGF15/19 signaling pathway antagonism.

Main Results:

  • FGF21 overexpression increased liver Cyp7a1 expression and enlarged the bile acid pool in mice.
  • FGF21 led to increased bile acid transit into the colon in cholecystectomized mice.
  • The mechanism involves FGF21 antagonizing FGF15/19 at the βKlotho/FGFR4 receptor, inhibiting suppression of Cyp7a1.

Conclusions:

  • Fibroblast growth factor (FGF) 21 plays a novel role in regulating bile acid metabolism.
  • FGF21 increases bile acid production and influences bile acid circulation.
  • These findings are relevant for understanding FGF21 analog effects in clinical settings.
Keywords:
Bile acid metabolismFGF19FGF21FGFR4βKlotho

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