br Acknowledgements This study was supported by National

Acknowledgements This study was supported by National Institutes of Health grant (R01GM104037), VA grant (BX002741), and Rutgers Busch grant.
Nuclear receptor FXR is the master regulator of bile acids homeostasis The farnesoid X receptor (FXR) belongs to a family of proteins known as nuclear receptors (NRs). 48 NR genes have been identified in the human genome and 49 in the mouse genome [71]. NRs are a group of ligand-activated transcription factors that mediate a wide range of physiological processes, including development, metabolism, and reproduction [71]. NRs mediate hormonal, metabolic and nutritional signals by promoting gene transcription in order to drive precise and coordinated functional responses and orchestrating a close cooperation between different organs. The structure of these receptors usually consists of an N-terminal DNA binding domain (DBD) and a C-terminal ligand-binding domain (LBD). The DBD is the most conserved region, containing two zinc finger motifs that allow the NR binding to a consensus AGGTCA-like DNA sequence (called responsive elements, REs). NRs bind to regulatory regions of target genes as a homodimer or heterodimer with the retinoid X receptor (RXR), acting in concert with co-activators and co-repressors in order to activate or repress gene expression [71]. In the absence of ligand, the NRs are often complexed on the 2-APB with co-repressor proteins. Upon ligand binding to the NR, the co-repressor complex dissociates, and co-activator proteins are recruited. Among the NR ligands fatty acids, oxysterols and BAs are included. This integration of environmental stimuli with specific transcriptional responses makes NRs central for whole-body physiology. Several of NRs were initially categorized as ‘orphan’ receptors because their natural ligands were unknown. Over the past 20years, novel ligands have been matched with their orphan parents, leading to the identification of various homeostatic pathways [109]. FXR was first described in 1995 by Forman and co-workers [30], as a product of NR1H4 gene. FXR was described as a NR activated by the farnesol derivative, a metabolic intermediate of the mevalonic pathway. FXR is involved in the biosynthesis of cholesterol, BAs, sterol compounds, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, steroid hormones, and farnesylated proteins. In following years, it became clear that FXR was activated by BAs and that it should be considered as the master regulator of bile acids homeostasis [70], [95]. BAs are amphipathic molecules synthesized exclusively in the liver in order to allow the efficient digestion and absorption of lipids, cholesterol, and fat-soluble vitamins after food ingestion. BAs are cholesterol derivatives and their synthesis is a multistep reaction that involves several enzymes in different hepatic cellular compartments, such as the cytosol, mitochondria, endoplasmic reticulum and peroxisomes [106]. This is the “classical” pathway and leads to an equal amount of cholic acid and chenodeoxycholic acid (CA and CDCA, respectively). The first step in the ‘classical’ pathway is the 7α-hydroxylation of cholesterol by the rate-limiting enzyme cytochrome P450 7A1 (CYP7A1). Alternative production of BAs occurs by 27-hydroxylase and it is responsible for the production of oxidized cholesterol that is converted predominantly to CDCA in the liver [9]. Before being release from the liver, BAs are conjugated with taurine or glycine to form less toxic and more hydrophilic bile salts [132]. Normally, under fasting conditions, BAs are stored in the gallbladder and after the postprandial stimulus, BAs are secreted into the small intestine, where they participate in the digestion of food. Ultimately, they are reabsorbed back through the portal circulation into the liver [62] thereby reducing the requirement for de novo BA synthesis. Through this pathway, 95% of the BAs are recycled, and only 5% of them are newly synthesized in the liver daily in order to sustain a proper BA pool in the organism and to bypass an over expenditure of energy required for their synthesis. In mouse models, altered BA signaling in the liver is associated with severe diseases, including the development of cholestasis and hepatocellular carcinoma (HCC) [18], [81]. The regulatory function of BAs is mainly a result of BA activation of various intracellular ligand-activated NRs, such as pregnane X receptor (PXR), the vitamin D receptor (VDR), the G protein–coupled bile acid receptor (TGR5) and FXR that orchestrate a tight control of BA production and circulation.