| セッション情報 |
The 4th International Forum
I Drug-associated GI Injury：Advances of the pathogenesis and recent clinical topics 1. Advances of the pathogenesis（a）Mucosal injury and prostaglandins
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| タイトル |
IFI-1a-2：Bile acid activated receptors regulates integrity of gastrointestinal mucosa
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| 演者 |
Fiorucci Stefano（Department of Surgery and Biomedical Sciences, University of Perugia, Italy） |
| 共同演者 |
Distrutti Eleonora（Azienda Ospedaliera, Italy） |
| 抄録 |
Bile acid-activated receptors are a family of membrane and nuclear receptors activated by bile acids. This family included the G-protein coupled receptor GP-BAR1 and at least four nuclear receptors（FXR, CAR, PXR and VDR）. Bile acid-activated receptors are highly expressed in the gastrointestinal tract and regulate essential functions involved in maintenance of mucosal integrity, nutrient absorption, microbiota composition and metabolism. FXR is a bile acid sensor in the hepato-biliary system, while GP-BAR1 senses secondary bile acids and modulates GLP-1 release in the intesttine. In the past few years we have shown both GP-BAR1 and FXR exert an important role in protecting against mucosal injury caused by NSAIDs. Indeed, gastrointestinal injury caused by exposure of mice to non-selective cyclo-oxygenase（COX）inhibitor is exacerbated by GP-BAR1 and FXR deletion. Analysis of molecular mechanisms underlying the protective effects of these receptors has shown that while protection is COX-independent both receptors modulate the expression/activity of enzymes involved in generating two well characterized gaseous mediators：nitric oxide（NO）and/or hydrogen sulphide（H2S）. Specifically protection of gastrointestinal mucosa exerted by FXR and GP-BAR1 agonists against injury caused by acetyl salicylic acid or COX-1 inhibitors is reversed by inhibitor of the H2S-generating enzyme, cystathionine gamma-lyase（CSE）. Molecular analysis of the promoter region of CSE shows the presence of four GP-BAR1 responsive elements at least one canonical responsive element for FXR. In vitro studies have shown that while NSAIDs might inhibit the expression/activity of CSE in the intestinal mucosa, GP-BAR1 and FXR ligands do the opposite. Taken together these data highly a role for bile acid activated receptors in maintaining intestinal homeostasis and suggest a potential clinical use of their agonists in protecting against intestinal injury caused by ASA or NSAIDs. |
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