In the upper part of the intestine

In the upper part of the intestine a small amount of conjugated BAs are reabsorbed via passive diffusion, whereas the part of BAs that escape enterohepatic circulation passes into the colon where they undergo bacterial conversions such as deconjugation, dehydroxylation or dehydrogenation, into secondary BAs. Around 95% of BAs are taken up in distal ileum by the apical sodium- dependent bile acid transporter (ASBT) and subsequently recirculate to the liver via the portal vein to inhibit CYP7A1 and CYP8B1 gene transcription and BA synthesis [6] (Fig. 1). BAs regulate whole-body lipid metabolism and therefore maintain lipid homeostasis directly through the activation of several nuclear receptors e.g. FXR, Pregnane X receptor (PXR) and vitamin D receptor (VDR), and G protein-coupled receptors, such as transmembrane G-coupled receptor 5 (TGR5) [12]. FXR and PXR are abundantly expressed in the liver and intestine, whereas VDR is widely distributed in most tissues including pancreas, skin, intestines, bones and the liver [13]. FXR is a nuclear hormone receptor which acts as a chief sensor of intracellular levels of BAs. The structure of BAs, particularly the location of hydroxyl groups in the carbon chain, determines their potency to bind and activate FXR. Generally, the more hydrophobic the BA is, the more affinity it possesses towards the FXR. The rank order from hydrophobic to hydrophilic BAs that corresponds to their affinity to FXR is as follows LCA > DCA > CDCA > CA > UDCA > MCA [14]. This receptor is composed of several domains including C-terminal ligand binding site, DNA-binding domain responsible for the transcription of strictly defined genes, as well as ligand-independent N-terminal transcriptase and ligand-induced trans-activation domains which allow interaction with regulatory proteins [6]. FXR can form a heterodimeric complex with a member of the nuclear receptor family, retinoid X receptor-α (RXRα), which further interacts with specific DNA elements on the promoter region of target genes. FXR regulates transcription of numerous genes controlling the synthesis, conjugation, transport and Benzoylhypaconitine mg of BAs [15]. In the synthesis process, FXR affects the BAs pool by inhibiting cholesterol CYP7A1, CYP8B1 and CYP27A1, or through the stimulation of the conjugation process by genes encoding bile acid:CoA synthase (BACS) and bile acid:amino acid transferase (BAT) [16]. In addition, FXR is responsible for the expression of the ileal bile acid-binding protein (IBABP) which binds the BAs in the ileum and reduces their concentration in the intracellular space [1]. The FXR not only plays a particularly important role in maintaining BA equilibrium in the body, but also affects multiple distinct metabolic cascades [17]. In line, FXR−/− mice exhibited deregulated BA metabolism but more interestingly they also presented abnormalities in glucose and lipoprotein metabolism, displayed weakened epithelial barrier function and aberrancies in ileal bacteria composition [18], [19]. FXR modulation also causes changes in the immune system. Activation of the FXR contributes to the release of IL1-β, IL-2, IL-6, tumor necrosis factor-α and interferon-γ which are examples of pro-inflammatory mediators [20]. Moreover, it modulates the expression of several crucial transporters participating in the transport of BAs into the ileal enterocytes brush border membrane, e.g. ASBT and fatty acid-binding protein 6 (FABP6), or from the intestine to the portal vein e.g. organic solute transporters α (OSTα) and β (OSTβ) [20]. Fibroblast growth factor (FGF19), and its orthologue in mice the fibroblast growth factor 15 (FGF15), also participates in controlling BA homeostasis. Following high intracellular BA concentration, FXR stimulates the production of FGF19 in enterocytes and causes its release to the portal venous circulation and hepatocytes where it inhibits CYP7A1 [21]. Impaired function of FGF19 may occur in chronic diarrhea patients with idiopathic bile acid malabsorption (BAM) [22]. A major indicator defining the level of BAs synthesis in the liver is a BA intermediate, the 7α-hydroxy 4-cholesten-3-one (C4). The serum level of C4 reflects the rate of hepatic BA synthesis and strongly correlates with CYP7A1 action. Recent studies have shown a significant inverse correlation between the levels of FGF19 and C4 in the liver in the serum of patients with chronic diarrhea, suggesting the role of both blood markers in diagnosis of this disorder. It has been speculated that this effect is a result of an impaired processing, release, or breakdown of FGF19, or improper response of the FGF19 receptor, fibroblast growth factor receptor 4 (FGFR4) or coreceptor β-klotho in the hepatocytes [23].