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ROLE OF THE FARNESOID X RECEPTOR (FXR) IN INTESTINAL EPITHELIAL CELL GROWTH AND DIFFERENTIATION
Y Robitaille, JC Carrier
Département d’anatomie et biologie cellulaire, Faculté de médecine et des sciences de la santé, Université de Sherbrooke
Farnesoid X receptor (FXR) is a member of the nuclear receptor super family that is physiologically activated by bile acid. FXR is expressed mostly in liver, adrenal gland, kidney and intestine. It plays a major role in bile acid homeostasis, lipoprotein metabolism and he is involved in entero-protection against bacterial proliferation. Elevated fecal concentrations of bile acid is associated with an increased incidence of colorectal cancer, moreover a decrease in FXR gene expression has been reported in colon cancer samples, as compared with normal mucosa. Theses observations suggest an implication for FXR in protecting epithelial cell of the colon against carcinogenesis. In addition, there are some evidences that FXR regulates epithelial cell differentiation and function as its expression could be detected in the differentiated cells of the crypt/villus axe and FXR deficiency in mice resulted in epithelial barrier disruption. Our aim is therefore to explore the role of FXR in intestinal epithelial cell growth and differentiation.
METHODS: We first stably re-express FXR in the DLD-1 colon cancer cell line and determine their growth potential in response to the GW4064 specific agonist. Second, the post-confluent Caco-2/15 epithelial cell differentiation model has been used and endogenous FXR has been activated by GW4064 followed by differentiation marker measurement. Third, differentiation potential has also been studied in post-confluent Caco-2/15 in which FXR has been decreased by stable expression of a specific shRNA.
RESULTS: Treatment by GW4064 of DLD-1 expressing FXR resulted in significant growth reduction as well as attenuation of the growth promoting effect of bile acids. Growth reduction has been associated with lower COX-2 expression. The activation of FXR in Caco 2/15 resulted in up regulation of occludin, a thigh junction protein, and other gene known as differentiation marker such as sucrase-isomaltase and alkaline phosphatase. Furthermore, the expressions of the same genes were significantly reduced in post confluent Caco-2/15 in which FXR was efficiently reduced by shRNA.
CONCLUSION: Taking together, theses results support a protective action of FXR against colon carcinogenesis through reduction of cell growth and promotion of intestinal epithelial differentiation.