Further research should indeed focus

Further research should indeed focus on understanding the nutritional value of food and its effect on metabolism, overall activation of metabolic NRs network. Moreover, given the prominent role of microbiota in the modulation of the FXR signalling (Degirolamo et al., 2014), there is enough impetus to address the relationship between microbiota and FXR in CRC. In conclusion, an impaired activation of the Apc-CDX2-FXR axis together with a harmful high fat/high carb diet will lead to increased levels of secondary toxic BA that in this context would not be detoxified thus driving acceleration and progression of CRC. The activation of intestinal FXR and the release of the gut hormone FGF19 could then be bona fide a novel biomarker of healthy nutritional status and eventually a putative therapeutic and/or adjuvant approach in CRC.
Bile acids and hepatocarcinoma (HCC) Bile acids (BAs) are amphipatic steroids able to facilitate the hsp90 inhibitors of dietary lipids and liposoluble vitamins. They represent the major system for cholesterol excretion in which cholesterol is removed from the body, as they are synthesized from cholesterol in the liver [1]. Altered BA signaling in the liver and intestine is associated with severe disease, including the development of inflammation and cholestasis with susceptibility to hepatocarcinoma (HCC). Indeed, despite their beneficial role in solubilizing lipophilic nutrients such as dietary fat, steroids and vitamins, thereby facilitating their intestinal absorption, high levels of BAs causes inflammation, DNA oxidative damage, cell proliferation and inhibits apoptosis, subsequently promoting neoplastic transformation of hepatocytes [2]. Thus, a tight regulation of BA concentration is essential for both cholesterol homeostasis and hepatic health [3,4]. In the liver, BAs are synthesized via a series of enzymatic reactions, initiated by a microsomal cholesterol 7α-hydroxylase (CYP7A1), which converts cholesterol to 7α-hydroxycholesterol, representing the rate-limiting step in the BA synthesis [5]. Before active secretion of BAs into the canalicular lumen, primary BAs are conjugated with taurine or glycine to form less cytotoxic bile salts, readily secretable into bile [6]. After postprandial stimuli, bile salts are released from the gallbladder into the small intestine and at the distal ileum and 95% of BAs are actively absorbed, returned back to the liver through the portal circulation, thus reducing the energy expenditure for de novo BA biosynthesis [7]. In the colon, primary BAs are transformed to secondary BAs (lithocholic acid, LCA and deoxycholic acid, DCA) through action of intestinal bacteria by a de-conjugation process and are then are passively absorbed by enterocytes, returned back to the liver where they are re-conjugated. Approximately 5% of the BA pool per day escape intestinal reabsorption and are excreted into the feces. This loss is accurately compensated by de novo synthesis in the liver in order to maintain the pool size which represent a major determinant of cholesterol turnover. Alterations in bile flow, due to defects in the bile formation process or caused by a physical obstruction in bile ducts are responsible for cholestatic liver disorders. Mutations in the ABCB11 gene causes progressive familial intrahepatic cholestasis (PFIC) type 2. The ABCB11 gene encodes for BSEP, the primary canalicular bile salt export pump which mediates the active transport of BAs into the canalicular lumen, generating bile flow [8]. Defective BA export leads to progressive cholestasis and Abcb11−/− mice, as expected, are characterized by progressive accumulation of hepatic BA, leading to liver injury [9]. The elevated BAs in this murine model induces changes in the metabolic state by disrupting glycolysis and gluconeogenesis and by alterations in the fatty acid oxidation. As a result, intracellular ROS are increased and causes liver inflammation, necrosis and fibrosis [10]. Defects in ABCB4 gene, encoding the multidrug resistance class III (MDR3) protein, cause the PFIC type 3 [11]. MDR3 is expressed in the canalicular membrane of hepatocytes and is mainly involved in phosphatidylcholine excretion in the bile [12]. ABCB4−/− mice are characterized by the absence of MDR3 protein, resulting in low biliary phospholipid levels that promote bile regurgitation into the portal tracts accompanied by spontaneous development of periportal biliary fibrosis and liver injury [13]. After 2–3 weeks of age, Abcb4−/− mice display inflammation, ductural proliferation and fibrosis, resulting in hepatocyte dysplasia at 4–6 months. These mice develop liver tumors in 16 months [14]. Thus, the regulation of these ABC transporters is crucial in order to avoid BAs overload and consequently liver injury and their concentrations require a tight regulation in order to prevent hepatic disease.