期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 306, 期 2, 页码 G163-G171出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00276.2013
关键词
gallbladder; ileum; intestine; signal transduction
资金
- [NIH NIDDK DK 54165]
- [NIH NIDA DA025088]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK054165] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA025088] Funding Source: NIH RePORTER
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.
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