c-Fos mediates repression of the apical sodium-dependent bile acid transporter by fibroblast growth factor-19 in mice

Am J Physiol Gastrointest Liver Physiol. 2014 Jan;306(2):G163-71. doi: 10.1152/ajpgi.00276.2013. Epub 2013 Dec 5.


Fibroblast growth factor-19 (FGF-19), a bile acid-responsive enterokine, is secreted by the ileum and regulates a variety of metabolic processes. These studies examined the signal transduction pathways operant in FGF-19-mediated repression of the apical sodium-dependent bile acid transporter (ASBT). Responses to FGF-19 were assessed in Caco-2 and CT-26 cells and in mice where c-fos was conditionally silenced in the intestine by a cre-lox strategy. FGF-19 treatment of Caco-2 cells or wild-type mice led to a significant reduction in ASBT protein expression and enhanced phosphorylation of extracellular signaling kinase 1/2 (ERK1/2), c-Fos, and c-Jun. FGF-19 treatment of Caco-2 cells led to a reduction in activity of the human ASBT promoter and this repression could be blocked by treatment with a mitogen-activated protein kinase/ERK kinase (MEK1/2) inhibitor or by silencing jun kinase 1, jun kinase 2, c-fos, or c-jun. Site directed mutagenesis of a c-fos binding element in the ASBT promoter blocked FGF-19-mediated repression in luciferase reporter constructs. ASBT promoter activity was repressed by FGF-19 in CT-26 cells and this repression could be reduced by MEK1/2 inhibition or silencing c-fos. FGF-19-mediated repression of ASBT protein expression was abrogated in mice where c-fos was conditionally silenced in the intestine. In contrast, ASBT was repressed in the c-Fos expressing gallbladders of the same mice. The studies demonstrate that FGF-19 represses the expression of ASBT in the ileum and gallbladder via a signal transduction pathway involving MEK1/2, ERK1/2, JNK1, JNK2, and c-Fos.

Keywords: gallbladder; ileum; intestine; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Butadienes / pharmacology
  • Caco-2 Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factors / pharmacology*
  • Flavonoids / pharmacology
  • Humans
  • Luciferases / genetics
  • Mice
  • Mitogen-Activated Protein Kinases / physiology
  • Nitriles / pharmacology
  • Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors*
  • Plasmids / genetics
  • Proto-Oncogene Proteins c-fos / physiology*
  • Proto-Oncogene Proteins c-jun / genetics
  • Signal Transduction / drug effects
  • Symporters / antagonists & inhibitors*
  • Transcription Factor AP-1 / physiology
  • Transfection


  • Butadienes
  • Enzyme Inhibitors
  • Flavonoids
  • Nitriles
  • Organic Anion Transporters, Sodium-Dependent
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Symporters
  • Transcription Factor AP-1
  • U 0126
  • fibroblast growth factor 15, mouse
  • sodium-bile acid cotransporter
  • Fibroblast Growth Factors
  • Luciferases
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one