Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage

Abstract

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.

Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells

“…Besides the intestinal system, kidneys, liver or adrenal glands, FXR exhibits a low expression level in the stomach, heart, lung and fat tissue (9,11,12,(27)(28)(29). In the present study, we observed FXR expression at a significantly lower level in cultured human GES-1 gastric mucosa cells and assessed the functional connection between bile acid-FXR pathway and intestinal metaplasia of gastric mucosa cells.…”

“…It was reported that activation of the FXR pathway in mice is able to resist the gastrointestinal mucosal damage of non-steroidal anti-inflammatory drugs (NSAIDs) (30). FXR functions to protect gastric epithelial cells against inflammation-mediated damage (11). Those findings suggest that proper stimulation of FXR serves as a type of protective mechanism for mucosa.…”

“…Bile acid, as an endogenous ligand, can induce FXR activation, which is involved in the abnormal growth of the digestive tract, chronic inflammatory disease, metabolic disease and carcinogenesis (7)(8)(9)(10)(11)(12).…”

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…The therapeutic potential of bile acids and derivatives for treating hepatic and biliary diseases, NAFLD, and metabolic syndrome has been extensively reviewed Fiorucci and Baldelli, 2009;Zollner and Trauner, 2009;Lian et al, 2011;Pols et al, 2011a,b;Adorini et al, 2012;Hollman et al, 2012;Stojancevic et al, 2012;McMahan et al, 2013;Mudaliar et al, 2013;Stepanov et al, 2013;Duboc et al, 2014) and will be briefly summarized. Bile acid sequestrants have long been used for treating gallstone disease.…”

“…It was concluded that FXR activation in the ileum is reduced in Crohn's patients, secondary to altered enterohepatic circulation of bile acids. TGR5 and FXR agonists may have therapeutic benefit to Crohn's disease patients (Lian et al, 2011;Pols et al, 2011b;Stojancevic et al, 2012;Stepanov et al, 2013).…”