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.
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Research Article|
August 12 2011
Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage
Fan Lian;
Fan Lian
*Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, 510275 Guangzhou, China
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Xiangbin Xing;
Xiangbin Xing
*Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, 510275 Guangzhou, China
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Gang Yuan;
Gang Yuan
*Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, 510275 Guangzhou, China
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Claus Schäfer;
Claus Schäfer
†Department of Medicine II, Klinikum der Universität München, D-81377 Munich, Germany
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Sandra Rauser;
Sandra Rauser
‡Institute of Pathology, Helmholtz Zentrum München, D-85764 Oberschleissheim, Germany
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Axel Walch;
Axel Walch
‡Institute of Pathology, Helmholtz Zentrum München, D-85764 Oberschleissheim, Germany
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Christoph Röcken;
Christoph Röcken
§Institute of Pathology, Christian Albrechts Universität, D-24105 Kiel, Germany
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Martin Ebeling;
Martin Ebeling
∥F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
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Matthew B. Wright;
Matthew B. Wright
∥F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
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Roland M. Schmid;
Roland M. Schmid
¶Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, D-81675 Munich, Germany
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Matthias P. A. Ebert;
Matthias P. A. Ebert
**Department of Medicine II, Universitätsklinikum Mannheim der Universität Heidelberg, D-68167 Mannheim, Germany
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Elke Burgermeister
**Department of Medicine II, Universitätsklinikum Mannheim der Universität Heidelberg, D-68167 Mannheim, Germany
To whom correspondence should be addressed (elke.burgermeister@lrz.tum.de).
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Publisher: Portland Press Ltd
Received:
December 15 2010
Revision Received:
May 25 2011
Accepted:
May 27 2011
Accepted Manuscript online:
May 27 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (2): 315–323.
Article history
Received:
December 15 2010
Revision Received:
May 25 2011
Accepted:
May 27 2011
Accepted Manuscript online:
May 27 2011
Citation
Fan Lian, Xiangbin Xing, Gang Yuan, Claus Schäfer, Sandra Rauser, Axel Walch, Christoph Röcken, Martin Ebeling, Matthew B. Wright, Roland M. Schmid, Matthias P. A. Ebert, Elke Burgermeister; Farnesoid X receptor protects human and murine gastric epithelial cells against inflammation-induced damage. Biochem J 1 September 2011; 438 (2): 315–323. doi: https://doi.org/10.1042/BJ20102096
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