FXR-mediated up-regulation of miR-29a-3p: implications for therapy of inflammatory bowel disease

Physiology 2015 (Cardiff, UK) (2015) Proc Physiol Soc 34, C15

Oral Communications: FXR-mediated up-regulation of miR-29a-3p: implications for therapy of inflammatory bowel disease

A. O Dwyer1, C. Greene1, S. Keely1

1. Royal College of Surgeons, Dublin, Ireland.

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Inflammatory bowel disease (IBD) is a group of intestinal disorders that results in chronic intestinal inflammation. Although the etiology of IBD is not yet fully understood, it is thought to arise due to an inappropriate mucosal immune response in genetically susceptible individuals. miRNAs are small, single stranded RNA molecules that regulate gene expression. The colonic epithelium of IBD patients has a unique miRNA expression profile, indicating the involvement of these molecules in disease pathogenesis. Farnesoid X receptor, FXR, is a nuclear bile acid receptor, activation of which has been shown to be protective in animal models of colitis by preserving integrity of the epithelial barrier (Gadaleta et al., 2011). Since the role of miRNAs in mediating FXR-mediated responses is not yet known, the aim of this study was to investigate the effect of the FXR agonist, GW4064 on miRNA expression in colonic epithelial cells. Isolated human colonic crypts and T84 colonic epithelial cells, were treated with GW4064 [5 mM] for 6 hrs. Use of human tissue was approved by the Beaumont Hospital Ethics Committee. RNA was extracted and miRNA profiling was performed by Nanostring Technologies. nCount software was used to detect miRNAs that were up-or down-regulated 1.5 fold or more compared to controls. TargetScan was used to identify miRNA targets. Validation of the miRNA array results, revealed that FXR activation increased expression of miR- 29a-3p by 3.9 ± 0.8 fold (n = 4; p < 0.05). This increase in miR- 29a-3p was mimicked by the natural FXR agonists, uUrsodeoxycholic acid (UDCA) [200 mM] and deoxycholic acid (DCA) [10 and 200 mM]. miR- 29a-3p [SK1] is predicted to target PTEN with a 92% context score as ascertained by TargetScan. Inhibition of PTEN has been well established to prevent epithelial cell apoptosis (Deevi et al., 2011). We found that treatment of colonic epithelial monolayers with GW4064 resulted in decreased PTEN mRNA (n = 8; p < 0.05) and decreased PTEN protein levels (n = 3; p < 0.05). [SK2] By virtue of their ability to increase expression of epithelial miR-29a-3p and reduce expression of its target PTEN, we hypothesise that FXR agonists may help to preserve intestinal barrier function by inhibiting apoptosis. Given the established importance of dysregulated barrier function in pathogenesis of IBD, our data suggest that FXR agonists represent a novel avenue for the development of new therapies for IBD.



Where applicable, experiments conform with Society ethical requirements.

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