br The bile acid farnesoid

The “bile acid” farnesoid X receptor (FXR) The Farnesoid X Receptor (FXR) is a ligand-activated nuclear receptor belonging to the Nuclear Receptor superfamily of transcription factors exploiting various crucial functions in mammalian physiology, including reproduction, development and metabolism (Mangelsdorf et al., 1995). There are two FXR genes: FXRα (NR1H4), highly expressed in the liver, ileum and adrenal gland in humans and mice, and FXRβ (NR1H5), expressed in dogs, rodents and rabbits while is a pseudogene in humans. (Zhang et al., 2003). Genome sequence analysis mapped FXRα gene onto chromosome 12q23.1 in humans, and chromosome 10c.2 in mouse, and consists of 11 exons and 10 introns (Huber et al., 2002). In this review, FXRα will be referred to as FXR. FXR is the master regulator of BA homeostasis (Makishima et al., 1999, Parks et al., 1999, Wang et al., 1999), governing their synthesis, transport and metabolism. Upon binding to BA, FXR venture a plethora of tissue-specific transcriptional activities governing the appropriate level and location of BA in the gut-liver axis (Fig. 1). In the liver, BA-dependent FXR activation primes the transcription of the small heterodimer partner (SHP), which in turn interacts with the liver receptor homologous-1 (LRH-1) (Goodwin et al., 2000, Lee and Moore, 2008, Lu et al., 2000), ultimately leading to reduced expression of CYP7A1, the rate-limiting enzyme of BA de novo synthesis. Also, hepatic FXR decreases BA cytotoxity by promoting the expression of BA CoA synthase (BACS) and BA-CoA-amino SC75741 sale N-acetyltransferase (BAAT) (Pircher et al., 2003, Solaas et al., 2000), two enzymes responsible of BA conjugation to glycine and taurine. Then, FXR promotes transport of BA and phospholipids into bile, through up-regulation of the Bile Salt Export Pump (BSEP/ABCA11) (Gerloff et al., 1998) and the multidrug resistance protein 3 (MDR3/ABCB4) (Huang et al., 2003), respectively, thereby ensuring the incorporation of BA into phospholipids micelles safeguarding the liver canaliculi from the intrinsic detergent property of BAs. After food ingestion, BAs are released into the duodenum, where they start their journey along the small intestine exploiting their major physiological functions. In the terminal ileum, 95% of BAs are then reabsorbed by the apical sodium-dependent bile acid transporter (ASBT) (Wong et al., 1995), shuttled from the apical to the basolateral enterocyte membrane by the intestinal BA binding protein (IBABP) (Gong et al., 1994, Tochtrop et al., 2004, Toke et al., 2006) and then secreted into the portal vein via the heterodimeric organic solute transporter OSTα/β (Dawson et al., 2005). Subsequently, they travel back to the liver where they are re-uptaken, closing the so-called enterohepatic circulation. All these genes are directly regulated by FXR. Most importantly, in the enterocytes, FXR bound to BAs induces the transcription of the fibroblast growth factor FGF15/19 (mouse and human, respectively), which is an enterokine secreted into the portal circulation that reaches the liver and by binding to its hepatic membrane receptor (FGFR4)/β-Klotho triggers a phosphorylation cascade in the c-jun N-terminal kinase-dependent pathway, ultimately inhibiting Cyp7a1 expression hence BA synthesis (Inagaki et al., 2005), a mechanism working in synergy with the hepatic FXR-SHP-dependent one (Kim et al., 2007a). This gut FXR-FGF15/19 action on the repression of hepatic BA synthesis represents one of the most intriguing systemic feedback regulatory loop (Degirolamo et al., 2016). It is also important to note that beyond their well known role of lipids emulsifiers and FXR ligands, as signalling molecules BA also activates the G-protein-coupled membrane receptor TGR5 (Maruyama et al., 2002). It has been recently shown its involvement in gastroesophageal carcinoma (Hong et al., 2010, Yasuda et al., 2007), however no evidence have yet been reported in colon cancer.