title: The G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Inhibits Gastric Inflammation Through Antagonizing NF-κB Signaling Pathway.
abstract: Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well-known for its roles in regulation of energy homeostasis and glucose metabolism. Here, we show that mice lacking TGR5 were much more susceptible to lipopolysaccharide (LPS)-induced acute gastric inflammation than wild-type (WT) mice and TGR5 is a negative regulator of gastric inflammation through antagonizing NF-κB signaling pathway. We found that the treatment of TGR5 ligands 23(S)-mCDCA and GPBARA (3-(2-Chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide) suppressed gene and protein expression mediated by NF-κB signaling. TGR5 overexpression with ligand treatment inhibited gene expression of interferon-inducible protein 10 (IP-10), TNF-α, and chemoattractant protein-1 (MCP-1) induced by LPS. Furthermore, we revealed that TGR5 activation antagonized NF-κB signaling pathway through suppressing its transcription activity, the phosphorylation of IκBα and p65 translocation, which suggests that TGR5 antagonizes gastric inflammation at least in part by inhibiting NF-κB signaling. These findings identify TGR5 as a negative mediator of gastric inflammation that may serve as an attractive therapeutic tool for human gastric inflammation and cancer.
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Guo
authors.affiliation: Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University Kaifeng, China ; Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University Hohhot, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Materials Science and Engineering, State University of New York at Stony Brook Stony Brook, NY, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing, China.
authors.forename: Qiqi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center Duarte, CA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center Duarte, CA, USA.
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University Kaifeng, China ; Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University Hohhot, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing, China.
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Wang
keywords: GPBAR1; GPCR; NF-κB; gastric inflammation; tgr5