The chemical structure of BAs

The chemical structure of BAs consists of a steroid nucleus with an acidic side chain. They are amphipatic molecules characterized by a hydrophilic α-face and a hydrophobic β-face. The hydrophobic pocket of the FXR LBD interacts with BAs largely through the β-face. The α-face contains several hydroxyl groups that impacts on the ability of each ligand to activate FXR [11]. Optimal FXR activation through ligand binding requires the proper repositioning of helix 3 versus helix 12 in order to generate the ligand binding pocket. BAs are not exclusively FXR ligands. With different efficiency they also activate other NRs, such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR) as well as the membrane G protein-coupled receptor TGR5 (reviewed in [12]). For this reason and taking advantage of the knowledge of the structure–activity relationship between BAs and FXR, semi-synthetic and synthetic molecules have been generated in order to obtain more selective and potent FXR activators than BAs. One of the most selective and powerful ligand is GW4064 [13]. This synthetic molecule is an FXR agonist active both in vitro and in vivo, however it displays a limited bioavailability that precludes the possibility of using it in clinical trials. Other FXR agonists, such as the semi-synthetic 6-Ethyl Chenodeoxycholic b catenin inhibitor (6-ECDCA) and FXR-450, are currently being tested in phase II/III clinical trials for metabolic and chronic liver diseases [14]. In a recent study, Mudaliar et al. have shown that the administration of 6-ECDCA derivate to patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease in phase II clinical trial increased insulin sensitivity and reduced markers of liver inflammation and fibrosis [15]. This demonstrates their safety and patients' tolerance to these drugs.
The bile acid enterohepatic circulation and FXR physiological actions
FXR mouse models
FXR in the regulation of lipid and glucose metabolism
FXR and cancerogenesis
Concluding remarks FXR is an important cell protector in the gut-liver axis and a central player in the complex pathogenetic mechanisms of metabolic diseases, hepatic and intestinal inflammation and carcinogenesis (Fig. 3). The development of tissue-specific transgenic mouse models increased our understanding in both the physiological and pharmacological actions of FXR. Now we know that FXR would definitively play a positive role in cholestatic liver disease as well as in hepatic inflammation and fibrosis with a putative antitumoral role in hepatocarcinoma. This action requires intestinal FXR activation and the gut-liver FGF15/19 axis. Furthermore, in the intestine FXR is able to maintain enterocyte homeostasis, mucosal fitness and eventually protect from colon cancer. Recent data are now opening a new avenue for the FXR area. The relationship with microbiota is capturing the attention of several laboratories in the field. The pinpoint question to solve in health and disease reveals two intriguing angles: bacteria modify BA profile and change FXR action in the gut and FXR pharmacological activation modulate bacteria growth [152], [153], species' variety and function. In addition, the latest discoveries on hepatic and intestinal FXR antitumoral actions might be the basis for novel therapeutic strategies that could prevent or delay tumor growth at early or advanced stages. Taken together, all these recent discoveries point at FXR as an intriguing pharmaceutical target for several disorders, such as cholestasis, diabetes, metabolic syndrome, chronic intestinal and hepatic inflammation and cancer. However, global FXR activation influences the expression of thousands of genes involved in metabolic homeostasis. Therefore, future directions for efficient drug discovery would benefit from the generation of selective FXR modulators, targeting subsets of FXR target genes or the bona fide pharmacological use of FXR direct targets such as the hormone FGF19.