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    • The effect of GC on Fgf was

    2022-03-09

    The effect of GC on Fgf21 was not directly dependent on ileal Fgf15 because basal Fgf21 hmg-coa reductase inhibitor was similar in Fgf15+/+ and Fgf15−/− mice. Moreover, GC treatment induced similar Fgf21 up-regulation in both strains. Fxr activation has been reported to increase Fgf21 expression and secretion [28]. In mice, neither the liver expression of the sensor (Fxr) nor the serum levels of the effectors (BA) were affected by GC, which does not support a role of this pathway in GC-induced hepatic Fgf21 up-regulation. Basal and GC-stimulated Fgf21 expression was similar in int-Gr+/+ and int-Gr−/− mice, which also rules out an indirect role of epithelial ileal Gr in GC-induced hepatic Fgf21 up-regulation, but points toward a role of Gr in the liver of both int-Gr+/+ and int-Gr−/− mice. It should be kept in mind that the expression of Gr was preserved in the liver of int-Gr−/− mice. A potential role of the activation at the intestinal and hepatic levels of the xenobiotic-sensor receptors Ahr, Car o Pxr at the dose of DEX used here cannot be ruled out, but our results and previous reports do not support this hypothesis. Thus, in rat liver, Ahr activation by its agonists can be enhanced by DEX but at doses much higher (10 mg/kg) than this used here [29]. In response to high fat diet, Pxr, but not Car, negatively regulates intestinal Fgf15 expression [30]. Treatment of mice with high doses of DEX (>20 mg/kg) resulted in Pxr, but not Car [31], activation, whereas the response to low doses (<6 mg/kg) was mainly mediated by triggering cell signaling through the Gr-mediated pathway [[32], [33], [34], [35]]. Our results are consistent with previous reports suggesting that DEX-induced Fgf21 up-regulation in mice can occur through a Pxr-independent mechanism [6], because, at a non-hepatotoxic dose, Pxr target genes, such as Cyp3a11, were not up-regulated both in liver and intestine, as could be expected [[34], [35], [36]]. In fact, we found marked Cyp3a11 down-regulation in mouse intestine. Moreover, results of the present study are consistent with previous studies by our group using HepG2 cells, in which we observed no change in the expression of the PXR target gene ABCC2 after treatment with DEX at non-toxic concentrations [1]. In rodents, Cyp7a1 expression can also be activated by Lxr [37, 38], which also binds to response elements in the Fgf21 promoter and interferes with its expression [39, 40]. However, it is unlikely that the effect of DEX observed here could have been mediated by Lxr because the expression of genes under the control of this nuclear receptor, such as Pgc1α in the liver [41] and Nhe3 in the intestine [42, 43] was not affected by DEX. PPARα is believed to play a major role in the regulation of FGF21 expression by hepatocytes. Activated GR and PPARα can promote in a synergistic manner the expression of genes accounting for erythroid progenitor self-renewal [44]. In support of the hypothesis that recruitment of GR and PPARα at the promoter region of FGF21 gene might be involved in GC-induced up-regulation we have found that in mice the expression of other typical Pparα target gene, such as Cyp4a14 [45], was also enhanced by treatment with DEX. Moreover, Gr activation also interfered, although in this case in a repressive way, with intestinal and liver expression of Vanin-1, which is sensitive to clofibrate, a typical PPARα agonist [46]. On the other hand, the results obtained regarding Cyp3a11 expression suggested that intestinal PPARα was activated, either by direct interaction with DEX or indirectly through Gr activation, because it has been reported that both clofibrate [47] and WY-14,643 [48] down-regulate Cyp3a11 in a PPAR-dependent manner, which does not occur in knockout mice for this nuclear receptor [47, 48]. Our results are consistent with previous studies by Patel et al. [49], who described that FGF21 and GC regulate their production in a feed-forward loop which provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation. These authors also suggested that, at least in mice, activated Gr binds to a non-canonical GC response element of the Fgf21 promoter region and cooperates with Pparα in stimulating Fgf21 expression [49].