Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage
| Autor: | Fan Lian, Martin Ebeling, Axel Walch, Gang Yuan, Elke Burgermeister, Sandra Rauser, Christoph Röcken, Claus Schäfer, Roland M. Schmid, Xiangbin Xing, Matthias P. Ebert, Matthew Blake Wright |
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| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty medicine.drug_class Receptors Cytoplasmic and Nuclear Apoptosis Biology Biochemistry Cell Line Mice chemistry.chemical_compound Stomach Neoplasms Internal medicine Chenodeoxycholic acid medicine Animals Humans Promoter Regions Genetic Receptor Molecular Biology Cell damage Inflammation Bile acid Keratin-13 Stomach Epithelial Cells Cell Biology Transfection medicine.disease Molecular biology Cytoprotection Gene Expression Regulation Neoplastic Mice Inbred C57BL Endocrinology chemistry Tumor necrosis factor alpha Farnesoid X receptor Disease Susceptibility Protein Binding |
| Zdroj: | Biochemical Journal. 438:315-323 |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | Bile acids from duodenogastric reflux promote inflammation and increase the risk for gastro-oesophageal cancers. FXR (farnesoid X receptor/NR1H4) is a transcription factor regulated by bile acids such as CDCA (chenodeoxycholic acid). FXR protects the liver and the intestinal tract against bile acid overload; however, a functional role for FXR in the stomach has not been described. We detected FXR expression in the normal human stomach and in GC (gastric cancer). FXR mRNA and protein were also present in the human GC cell lines MKN45 and SNU5, but not in the AGS cell line. Transfection of FXR into AGS cells protected against TNFα (tumour necrosis factor α)-induced cell damage. We identified K13 (keratin 13), an anti-apoptotic protein of desmosomes, as a novel CDCA-regulated FXR-target gene. FXR bound to a conserved regulatory element in the proximal human K13 promoter. Gastric expression of K13 mRNA was increased in an FXR-dependent manner by a chow diet enriched with 1% (w/w) CDCA and by indomethacin (35 mg/kg of body weight intraperitoneal) in C57BL/6 mice. FXR-deficient mice were more susceptible to indomethacin-induced gastric ulceration than their WT (wild-type) littermates. These results suggest that FXR increases the resistance of human and murine gastric epithelial cells to inflammation-mediated damage and may thus participate in the development of GC. |
| Databáze: | OpenAIRE |
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