Transmembrane G protein-coupled receptor (TGR5) may work in opposition to the effects of nuclear farnesoid X receptor (FXR) in the small intestine
Abstract
Objective: Activation of the dedicated bile acid receptors transmembrane G protein-coupled receptor (TGR5) and the nuclear farnesoid X receptor (FXR) induces differential effects on the intestinal epithelium. We hypothesize... [ view full abstract ]
Objective: Activation of the dedicated bile acid receptors transmembrane G protein-coupled receptor (TGR5) and the nuclear farnesoid X receptor (FXR) induces differential effects on the intestinal epithelium. We hypothesize that TGR5 acts in opposition to FXR in the small intestines.
Methods: We treated IEC-6 cells with the TGR5 specific agonist oleanolic acid (OA, 0.01-10 µM). Proliferation was measured with EdU and crystal violet staining and TGR5 levels were reduced with siRNA knockdown. In vivo, we used a mouse model of lipopolysaccharide (LPS) induced barrier dysfunction where mice are injected with LPS or saline via intra-peritoneal route to induce intestinal injury and gavage-fed FITC-dextran with or without OA 100mg/kg. Serum FITC levels and mRNA expression by RT-PCR were determined to assess barrier function.
Results: Proliferation increased by 25% at OA 1µM in IEC-6 cells, similar to taurocholic acid (TCA) treatment alone. TGR5 siRNA knockdown blocked TCA-induced proliferation. FXR inhibits proliferation, as we have previously shown. OA did not appear to protect the intestinal barrier in wild-type (WT) mice, but did decrease barrier breakdown in FXR knock-out (FXR-KO) mice. In WT and FXR KO mice, TGR5 mRNA expression was upregulated in mice treated with OA. LPS increased FXR mRNA expression in WT but not in FXR-KO.
Conclusions: OA stimulates intestinal cell proliferation and it protects the intestine most effectively in the absence of FXR. These data suggest that TGR5 and FXR work in opposition to one another and this activity may uncover novel therapeutic targets for regulating the intestinal epithelium during injury.
Authors
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Michael Mallicote
(Children's Hospital Los Angeles)
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Oswaldo Escobar
(Children's Hospital Los Angeles)
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Avafia Dossa
(Children's Hospital Los Angeles)
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Christopher Gayer
(Children's Hospital Los Angeles)
Topic Areas
Pediatric Surgery , Other
Session
Plenary » Plenary Scientific Session (10:25 - Friday, 22nd September, Bradley Lecture Center)