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    • br FXR FGF in the control of BAs synthesis

    2021-10-15


    FXR–FGF15/19 in the control of BAs synthesis The nuclear receptor FXR is the master regulator of BAs homeostasis, modulating their synthesis, SB 225002 and uptake [15]. FXR decreases BA de novo hepatic biosynthesis by reducing the expression of CYP7A1. At the canalicular membrane, newly-synthesized BAs are conjugated under regulation of FXR through the activation of the BA-CoA-synthase (BACS) and BA-CoA-amino acid N-acetyltransferase (BAAT) enzymes [16]. Conjugated BAs are then secreted into the gallbladder by the bile salt export pump (BSEP/ABCA11) and the multidrug related protein 2 (MRP2/ABCC2). The expression of these genes is under the control of FXR. After postprandial stimuli, BAs are secreted into the intestine. In the ileum, Apical Sodium-dependent Bile Acid Transporter (ASBT) determines the uptake of BAs, while IBABP is responsible for BAs transport from the apical to the basolateral membrane [17, 18, 19]. BAs are secreted in the portal blood by the heterodimeric organic solute transporter α/β (OST α/β). Post secretion, BAs are transported back to the liver, where a great majority is reabsorbed by the sodium (Na)-Taurocholate Cotransporter Protein (NTCP) and organic anion transporting polypeptide (OATP), both negatively regulated by FXR, thereby limiting the increase of hepatic BA levels. Finally, BAs are re-secreted into the bile [7], closing up the BAs enterohepatic circulation. Clearly, FXR represents the sensor of intracellular BA concentration in the hepatocytes, being able to transcriptionally regulate both secretion or excretion and their uptake or emittance. Nevertheless, this control by FXR is not limited to the liver. Indeed, FXR is highly expressed in the gut and have been identified as a key regulator of the gut–liver cross talk. In the ileum, BA-dependent FXR activation induces the production and secretion of the fibroblast growth factor FGF15 (mouse) and 19 (humans) in the portal circulation. FGF19 is an endocrine hormone that is able to repress CYP7A1 expression in the liver and thus reduces BAs synthesis. FGF19 binds the receptor FGFR4 with the coreceptor βklotho, triggering downstream signaling cascades [20, 21, 22]. Studies employing chimera of FGF19 protein have revealed that the C-terminus region is responsible for the binding to β-klotho, whereas the N-terminus appears to be important for FGFR activation [23]. The FGF15/19 mechanism of action seems to involve the extracellular signal-related kinase (ERK)1/2/mitogen-activated protein kinase (MAPK) pathway as a mediator of FGF15/19 inhibitory effect on BA synthesis [23] (Figure 1). However, the molecular mechanisms downstream of the FGF15/19–FGFR4–β-klotho complex are not fully understood. The relative contribution of hepatic and intestinal FXR in mediating CYP7A1 repression was shown through tissue-specific FXRKO murine models, where a more determinant role of intestinal FXR was revealed [24]. This mechanism represents an important crosstalk between intestine and liver for the regulation of BA synthesis.
    The protective role of FXR against HCC HCC is among the most lethal and prevalent human tumors and to date the therapeutic options are limited [25]. Recent findings have clearly indicated that FXR might be implicated in liver tumorigenesis [3,4,26]. Indeed, FXR has been shown to prevent oxidative damage, inflammation and resistance to apoptosis induced by chronic high accumulation of BAs [27]. The important role of FXR in the control of BA metabolism was initially demonstrated in FXR-null mice which are unable to maintain control of BA synthesis and transport. These mice display a deregulation of the CYP7A1 and IBABP genes upon CA-supplemented diet, with subsequently inactivation of the hepatic canalicular secretion, increases of BA hydrophilicity and urinary and fecal BA loss, leading to enlarged BAs pool size [28]. Furthermore, FXR-null mice exhibit high levels of the pro-inflammatory cytokines IL-1β, β-catenin and c-Myc at 3 months of age. The up-regulation of pro-inflammatory cytokines, resistance to apoptosis and cell hyperproliferation induced by increased BA pool size in the FXR-null mice results in spontaneous HCC development between 12 and 15 months of age [26,29, 30, 31].