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  • br FXR expression in normal intestine and cancer Of


    FXR leukotriene receptor antagonist in normal intestine and cancer Of note, there are several question marks about FXR post-translational modifications (such as acetylation or SUMOylation) and their involvement in the pathogenesis of metabolic and inflammatory disease (Balasubramaniyan et al., 2013, Kemper et al., 2009, Kim et al., 2015, Seok et al., 2013). Since all studies describing such modifications and their dysregulation have been focusing on the liver, in the future it would be important to verify their involvement in CRC onset or progress.
    Bile acids and FXR function in normal intestine and cancer As previously mentioned, studies in CRC mouse models have linked elevated fecal BA levels to increased CRC incidence thus identifying secondary BAs as major dietary-related factors in colon carcinogenesis. Moreover, population-based studies have shown that subjects who consume a Western diet display elevated levels of fecal secondary BAs (BAs), as do patients diagnosed with colonic carcinomas (Bajor et al., 2010, McGarr et al., 2005). Several studies have, in fact, indicated that this might be due to a lack of dietary fibers that would otherwise dilute carcinogens in the gut by increasing the stool bulk and modify the metabolism of these compounds. Concomitantly, excessive presence of high dietary fat will increase primary leukotriene receptor antagonist BA production, their microbiota-dependent transformation into secondary BA with high intracolonic BA concentrations as the final readout (reviewed in (Reddy, 1981)). Taken together, this evidence indicates that a detrimental diet may overstimulate secondary BA spilling into the large intestine where they would act as tumor promoters. Although apoptosis appears to be the normal response to BA exposure, resistance to BA-induced apoptosis has been linked to CRC development. Being FXR the master regulator of BA homeostasis and given the association between abnormal BA levels and CRC, researchers have produced a large body of evidence suggests a role for FXR in intestinal tumorigenesis. Given the crucial role of FXR in maintaining BA concentrations within a physiological range, thereby preventing BA-induced cytotoxicity, loss of FXR is associated with a pro-tumorigenic phenotype. Elevated secondary BA concentrations exert detrimental effects on colonic epithelium architecture and function through multiple mechanisms involving DNA oxidative damage, inflammation, NF-kB activation and enhanced cell proliferation (Fig. 1) (Bajor et al., 2010, Pearson et al., 2009). BA roles as tumor promoters have been tested using a wide variety of experimental settings, including feeding BAs before, in association with, or after carcinogen exposure. However, it is the absence of FXR from the intestinal epithelium and not merely elevated bile acid concentrations per se the cause of increased CRC susceptibility. In fact, susceptibility of FXR knockout mice to intestinal tumorigenesis was found unaffected by cholestyramine-mediated reduction in circulating BA levels (Modica et al., 2008). High levels of secondary BAs can instead worsen the deleterious cycle by increasing apoptosis of normal and fully differentiated enterocytes, expressing normal FXR levels and exert a pressure for the selective growth of less differentiated enterocytes presenting with low FXR expression and therefore resistant to apoptosis (Modica et al., 2008, Barrasa et al., 2013). As previously described, FXR mediates the signalling activity of BAs while regulating their metabolism. Intestinal and hepatic FXR activation induces the fibroblast growth factor Fgf15/FGF19 (Holt et al., 2003) and SHP (Goodwin et al., 2000), respectively, which synergistically inhibits BA synthesis. Simultaneously, FXR activation induces BA detoxification enzymes such as aldo-keto reductase 1 B7 (AKR1B7), cytochrome P450 3A4/3a11 (CYP3A4/Cyp3a11), cytosolic sulfotransferase 2A1 (SULT2A1) and UDP-glycosyltransferase 2B4 (UTG2B4) [reviewed in (Modica et al., 2009)]. The negative regulatory feedback of BA synthesis and their detoxification is vital given the hepatic and intestinal pro-tumorigenic potential of high levels of circulating BA (Modica et al., 2008, Degirolamo et al., 2015, Kim et al., 2007b, Yang et al., 2007).