br The Farnesoid X receptor

The Farnesoid X receptor (FXR): identification and ligands The Farnesoid X receptor (FXR) belongs to a family of proteins called Nuclear Receptors (NRs). NRs are a class of ligand-activated transcription factors, which transactivate networks of target genes, thereby mediating a wide range of physiological processes, including development, metabolism, and reproduction [1]. Upon activation by specific ligands (hormones, vitamins, lipophilic metabolites and dietary lipids), NRs promote gene transcription with precise and coordinated functional responses and close cooperation of different organs. The NR superfamily comprises 48 members. Each receptor has a peculiar role in the regulation of several biological processes. NRs share a common structure, and consist of a highly conserved DNA binding domain (DBD), responsible for the binding of NRs on DNA specific sites called responsive elements (REs); a ligand binding domain (LBD), a hydrophobic pocket for ligand identification and lodging; and a variable hinge region connecting the DBD and the LBD. In the absence of ligand, NRs are often complexed on the UNC1999 synthesis with co-repressor proteins. Then, ligand binding to NRs causes dissociation of co-repressor and recruitment of co-activator proteins. Additional proteins of the basal transcriptional machinery, including RNA polymerase II, are subsequently recruited to the NR/DNA complex in order to start the transcription process. In 1995, a protein called RXR-interacting protein 14 (RIP14) was discovered in mice [2]. In the same year, an independent group cloned the RIP14 rat homologue, and showed that superphysiological levels of farnesol (an intermediate of the mevalonate pathway) were able to activate it [3]. Since then, RIP14 was named Farnesoid X receptor (FXR). Later, in 1999, it was demonstrated that primary BAs are the natural FXR ligands and, for this reason, FXR was also named Bile Acid Nuclear Receptor (BAR) [4], [5], [6]. As a NR, FXR has a well-characterized structure: a moderately conserved C-terminal LBD, and a highly conserved DBD. FXR responsive elements (FXREs) consist of an inverted repeat sequence of the canonical AGGTCA separated by one nucleotide (IR-1), although other variations have been observed, such as directed repeats DR-1 and everted repeats ER-8. In the absence of ligands, FXR is bound in an inactive state to FXREs of its own target genes as a heterodimer with his obliged partner RXR, in association with co-repressor proteins. Upon BAs binding, a conformational change of the protein complex occurs, and transcription-repressing proteins [e.g. nuclear receptor co-repressor 1 (NCoR)] are released. Subsequently, transcription-activating proteins [e.g. co-activator-associated arginine methyltransferase 1 (CARM1)] [7] and the basal transcriptional machinery are recruited to the FXRE, thereby starting target genes transactivation. According to its major function of master regulator of BA homeostasis, FXR has been shown to have a specific tissue distribution, along the entire gastrointestinal tract with a peak in the liver and ileum, as well as in the kidney, and adrenal glands [3], [8]. Low FXR expression profiles have been detected in the heart, adipose tissue [9] and some hormone-responsive tissue, such as the breast [10]. The most powerful FXR natural ligands are the two major natural BAs, Chenodeoxycholic and Cholic Acids (CDCA and CA, respectively) [4], [5], [6]. BAs are detergent-like molecules synthesized from cholesterol in the liver, stored in the gallbladder, and released into the intestine after food intake to facilitate the absorption of dietary lipids and liposoluble vitamins. BAs are extensively recycled in the body in a cycle called enterohepatic circulation (Fig. 1). In fact, they are reabsorbed in the terminal ileum, secreted into the portal vein, and subsequently travel back to the liver, where they are reabsorbed. In this way, 95% of BAs are recycled, and only 5% of them are newly synthesized in the liver daily. In this way the organism maintains a proper BA pool and circumvents an overexpenditure of energy required for their synthesis.