title: c-Fos mediates repression of the apical sodium-dependent bile acid transporter by fibroblast growth factor-19 in mice.
abstract: 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.
authors.affiliation: Children's Hospital of Pittsburgh of UPMC, Division of Pediatric Gastroenterology, Hepatology and Nutrition, 4401 Penn Ave., Pittsburgh, PA 15224. benjamin.shneider@chp.edu.
authors.forename: Ayantika
authors.initials: A
authors.lastname: Ghosh
authors.forename: Frank
authors.initials: F
authors.lastname: Chen
authors.forename: Swati
authors.initials: S
authors.lastname: Banerjee
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D010957:Plasmids / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D027981:Symporters / Q000037:antagonists & inhibitors*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014162:Transfection
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D029363:Organic Anion Transporters, Sodium-Dependent; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D027981:Symporters; D018808:Transcription Factor AP-1; C113580:U 0126; C108526:fibroblast growth factor 15, mouse; C071908:sodium-bile acid cotransporter; D005346:Fibroblast Growth Factors; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: gallbladder; ileum; intestine; signal transduction