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FGF19 (fibroblast growth factor 19) as a novel target gene for activating transcription factor 4 in response to

Makoto Shimizu1, Juan Li, Ryuto Maruyama

  • 1Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.

The Biochemical Journal
|December 5, 2012
PubMed

Insights

Endoplasmic reticulum stress inducers, like thapsigargin, increase fibroblast growth factor 19 (FGF19) expression in intestinal cells. This occurs via the activating transcription factor 4 (ATF4) pathway, independent of the farnesoid X receptor.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Fibroblast growth factor 19 (FGF19) is an enterohepatic hormone regulating bile acid synthesis and metabolism.
  • Identifying novel regulators of FGF19 expression beyond bile acids is crucial for understanding metabolic control.

Purpose of the Study:

  • To investigate novel agents that induce fibroblast growth factor 19 (FGF19) expression.
  • To elucidate the molecular mechanism by which endoplasmic reticulum (ER) stress influences FGF19 production.

Main Methods:

  • Incubation of Caco-2 cells with ER stress inducers (thapsigargin).
  • Analysis of FGF19 mRNA and protein levels.
  • Reporter gene assays to identify functional promoter elements.
  • Electrophoretic mobility-shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) to assess protein-DNA interactions.
  • Overexpression and knockdown studies of ATF4.

Main Results:

  • Thapsigargin significantly increased FGF19 mRNA and secreted protein levels in Caco-2 cells.
  • A functional amino-acid-response element (AARE) in the FGF19 promoter was identified.
  • Activating transcription factor 4 (ATF4) was found to bind the AARE and mediate ER stress-induced FGF19 transcription.
  • ATF4 overexpression elevated FGF19 mRNA, while ATF4 depletion attenuated thapsigargin-induced FGF19 expression.

Conclusions:

  • Endoplasmic reticulum (ER) stress, induced by thapsigargin, upregulates FGF19 expression in intestinal cells.
  • The ATF4 transcription factor plays a key role in mediating ER stress-induced FGF19 production via an AARE in its promoter.
  • This pathway for FGF19 regulation is independent of the farnesoid X receptor.

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