Abstract
So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5'-O-3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.
MeSH terms
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Amino Acid Sequence
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Animals
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Bile Acids and Salts / chemistry*
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Bile Acids and Salts / metabolism
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CHO Cells
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Cell Line
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Cell Membrane / metabolism
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Cricetinae
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Cyclic AMP / metabolism
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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GTP-Binding Proteins / chemistry*
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Genetic Vectors
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Green Fluorescent Proteins
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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Luminescent Proteins / metabolism
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MAP Kinase Signaling System
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Macrophages / metabolism
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Sequence Data
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Phagocytosis
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Protein Binding
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RNA, Messenger / metabolism
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Rabbits
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Rats
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / metabolism*
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Receptors, G-Protein-Coupled*
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Tissue Distribution
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Transfection
Substances
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Bile Acids and Salts
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Cytokines
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GPBAR1 protein, human
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Gpbar1 protein, mouse
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Luminescent Proteins
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Guanosine 5'-O-(3-Thiotriphosphate)
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Cyclic AMP
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Mitogen-Activated Protein Kinases
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GTP-Binding Proteins
Associated data
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GENBANK/AB089306
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GENBANK/AB089307
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GENBANK/AB089308
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GENBANK/AB089309
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GENBANK/AB089310