It has been proposed that bile acidity suppression of CYP7A1 gene

It has been proposed that bile acidity suppression of CYP7A1 gene manifestation is mediated through a gut-liver signaling pathway fibroblast development element (FGF)15/19-fibroblast growth element receptor 4 which is set up by activation of farnesoid X receptor in the ileum however, not in the liver organ. using the designated boost of FGF15/19 mRNA amounts in the ileum or inhibited CYP7A1 manifestation in the S0859 IC50 liver organ. Further, in Ch-fed rats, CYP7A1 mRNA improved 1.9-fold (< 0.001) although FGF15 mRNA amounts in the ileum and website blood FGF15 proteins levels weren't decreased. In Ch-fed rabbits, although FGF19 mRNA amounts in the ileum and liver organ did not increase significantly, CYP7A1 mRNA declined 49% (< 0.05). We were unable to find corresponding changes of FGF15/19 protein levels in the portal blood in rats and rabbits where the mRNA levels of FGF15/19 in the ileum and CYP7A1 in the liver change significantly. expression in the liver, which in turn inhibits LRH-1-mediated transcriptional activation of the gene (4, 5). This hypothesis, involving a cascade reaction in the liver, provides an explanation at the molecular level for the indirect repression of CYP7A1 by bile acid-activated FXR. Our results from in vivo studies in rabbits (6C8) and rats (9) agree with the hypothesis that activation of hepatic FXR by the increased circulating enterohepatic bile acid pool plays an essential part in the downregulation of CYP7A1 manifestation. Pandak et al. (10) reported that intravenous perfusion of taurocholate via the inner jugular vein didn't downregulate CYP7A1 manifestation in rats with bile fistula and suggested that there must be an intestinal element which is essential for the downregulation of CYP7A1. When the bile duct was ligated in rats (11) or mice (12), where bile acids gathered in the liver organ and didn't reach the intestine, CYP7A1 manifestation unexpectedly improved indicating a job for the intestine in rules of CYP7A1. Furthermore, it had been recommended that bile acids infused through peripheral (10, 13, 14) and S0859 IC50 portal venous systems (15) didn't exert feedback rules to downregulate CYP7A1/bile acidity synthesis in rats. Lately, an alternative solution hypothesis was suggested that CYP7A1 gene manifestation was controlled from the gut-hepatic sign fibroblast growth element (FGF)15 indicated in the intestine via the ileal FXR-FGF15-FGF4 receptor pathway (12). FGF15 in mice (12), or its ortholog FGF19 in human beings (16), may S0859 IC50 be the focus on gene of FXR. In mice, FGF15 is principally indicated in the ileum however, not in the liver organ (12), while FGF19 is indicated in the hepatocytes (17, 18). Therefore, it's been suggested that FGF15 can be selectively induced by bile acids-FXR in the ileum that works as an intestinal-hepatic sign through FGF receptor 4 (FGFR4) getting together with SHP to repress CYP7A1 manifestation in the liver organ (12, 16). Furthermore, it had been demonstrated that activation from the FXR-FGF15 pathway in the intestine, however, not activation of FXR-SHP in the liver organ, suppresses CYP7A1 gene manifestation (19). Recently, Kong et al. (20) reported that both FGFR4 and SHP are in charge of suppressing manifestation in the liver organ of mice after activation of FXR, but FGFR4 appears more important. Regardless of the above results, it isn't known whether FGF15/19 proteins amounts in the portal bloodstream reflect changes of FGF15/19 gene expression in the ileum to reach the liver and control the gene expression of CYP7A1. In the present study we investigated this relationship. MATERIALS AND METHODS Animal experiments In this study, rats and rabbits were fed cholesterol (Ch)- or cholic acid (CA)-containing chow respectively, as these treatments have been shown to cause significant changes in activation of FXR in the ileum and liver and hepatic gene expression of CYP7A1 in these animals. Sprague Dawley rats (n = Tfpi 24), males weighing around 250 g were divided into three different groups (n = 8): rats fed regular chow (control), 2% Ch, and 1% CA respectively for 7 days. On the seventh feeding day, rats were euthanized around 12:00 PM, 4 h after the dark cycle was started (8:00 AMC8:00 PM). Portal and peripheral blood, ileal mucosa, and liver tissues were collected immediately under anesthesia [ketamine (60 mg/kg) + xylazine (6 mg/kg) im] right before euthanasia. New Zealand white rabbits (n = 24) were assigned into three experimental groups (n = 8) and fed chow (control), 2% Ch, and 0.3% CA for 7 days. The rabbits were fed 4 ounces of chow every day at 8:00 AM under light cycle (7:00 AMC7:00 PM). After completing the treatments, the rabbits were euthanized under.

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