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    • VO-Ohpic trihydrate sale According to its major function as

    2022-06-21

    According to its major function as master regulator of BA homeostasis, FXR has been shown to have a specific tissue distribution; it is expressed along the entire gastrointestinal tract with a peak in the liver and ileum, as well as in the kidney, and adrenal glands [30], [66], [135]. Low FXR expression profiles have been detected in the heart, adipose tissue [148] and in some hormone-responsive tissues, such as the breast [122]. The important role of FXR in regulating BA synthesis was initially shown in FXR-/- mice. These transgenic animals exhibit an increased BA pool size combined with an increased expression of pro-inflammatory cytokines, resistance to apoptosis and cell hyperproliferation that lead to spontaneous HCC development between 12 and 15months of age [51], [55], [111], [142].
    FXR in the gut-liver axis: orchestrating the bile acids metabolism The regulation of BA concentrations within hepatocytes, enterocytes and in the enterohepatic circulation is orchestrated by tissue-specific FXR activities via an intensive molecular cross-talk between the liver and the intestine. FXR influences BA flux via various feedforward and feedback loops: it decreases BA de novo synthesis in the liver, while it increases BA secretion into the small intestine. In the liver, FXR-activation induces the expression of the small heterodimer partner (SHP), which interacts with the liver receptor homologous 1 (LRH-1), repressing its activity [36], [61], [65]. As a consequence, SHP-LRH-1 interaction results in a CYP7A1 reduced expression, ultimately decreasing BA synthesis. In a similar manner, via SHP-mediated repression through the hepatocytes nuclear factor 4α (HNF4α), FXR inhibits another critical cytochrome, the CYP8B1, which regulates the ratio between CA and CDCA [146]. Newly-synthesized BAs are conjugated with taurine or glycine, and FXR regulates these important processes inducing the BA CoA synthase (BACS) and BA-CoA-amino VO-Ohpic trihydrate sale N-acetyltransferase (BAAT) [114], two enzymes responsible for BAs conjugation. Conjugated BAs are then actively secreted in the canaliculi by the bile salt export pump (BSEP/ABCA11) and the multidrug related protein 2 (MRP2/ABCC2) and stored in the gallbladder. These transporters belong to the ABC transporter family and are both induced by FXR at transcriptional level. Moreover, FXR activation also induces the expression of the multidrug protein 3/2 (MDR3/Mdr2, ABCB4/Abcb4), another ABC transporter involved in the biliary secretion of phosphatidylcholine [79].The regulation of these ABC transporters is crucial in order to avoid BA accumulation in the liver and, consequently, hepatic injury. Indeed, mutations in the BSEP and MDR3 proteins are responsible for two different type of progressive familial intrahepatic cholestasis (PFIC) [119] [17]. The FXR-dependent concomitant activation of BSEP and MDR3 has an extensive and protective physiological role avoiding BA cytotoxicity by their incorporation into phospholipid micelles. After fat ingestion, the hormone cholecystokinin is released from the proximal intestinal tract, causing gallbladder contraction and bile delivery into the small intestine. The bile travels along the intestine and at the distal ileum, the majority of the BAs are actively absorbed and returned to the liver through the portal vein, to be re-secreted into the bile [64], in a process called enterohepatic circulation. During this event, in the distal intestine conjugated BAs undergo a de-conjugation process by bacterial enzymes, allowing unconjugated BAs to cross the plasma membrane via passive diffusion. In addition, BAs are also actively reabsorbed by the Apical Sodium-dependent Bile Acid Transporter (ASBT) [141]. In the ileum, BA-dependent FXR activation induces the fibroblast growth factor FGF15/19 (mouse and human, respectively), a hormone secreted in the portal circulation that is able to reach the liver and to bind to the fibroblast growth factor receptor 4 (FGFR4)/β-Klotho complex. FGF15-FGFR4/β-Klotho binding triggers the c-jun N-terminal kinase-dependent pathway [43], which ultimately leads to CYP7A1 repression. This mechanism constitutes an important crosstalk between intestine and liver in the regulation of BA synthesis. Moreover, the use of tissue-specific liver- or intestine-FXR-/- mice displayed the relative contribution of hepatic and intestinal FXR in the repression of CYP7A1 and indicated a more determinant role for the intestinal FXR [50]. In the enterocytes, BAs are shuttled from the apical to the basolateral membrane by the intestinal BA binding protein (IBABP) [35], [123], [124], although the precise biological function of IBABP is not clear [85].