Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage
Résumé
Bile acids from duodenogastric reflux promote inflammation and increase the risk for gastro-esophageal cancers. Farnesoid X receptor (FXR) is a transcription factor regulated by bile acids, such as chenodeoxycholic acid (CDCA). 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 gastric cancer (GC). FXR mRNA and protein were also present in the human GC cell lines MKN45 and SNU5 but not in AGS. Transfection of FXR into AGS cells protected against TNFa-induced cell damage. We identified Keratin 13 (K13), 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 i.p.) in C57BL/6 mice. FXR-deficient mice were more susceptible to indomethacin-induced gastric ulceration than wild-type littermates. These data 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.
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