Department of Medicine, New Jersey Medical School, Newark, NJ 07103.
J Lipid Res. 2013 Oct;54(10):2606-14. doi: 10.1194/jlr.M034827. Epub 2013 Jul 12.
It has been proposed that bile acid suppression of CYP7A1 gene expression is mediated through a gut-liver signaling pathway fibroblast growth factor (FGF)15/19-fibroblast growth factor receptor 4 which is initiated by activation of farnesoid X receptor in the ileum but not in the liver. This study evaluated whether FGF15/19 protein levels in the portal blood reflected changes in FGF15/19 mRNA in the ileum. Studies were conducted in Sprague Dawley rats and New Zealand white rabbits fed regular chow (controls), supplemented with cholesterol (Ch) or cholic acid (CA). After feeding CA, ileal FGF15 mRNA increased 8.5-fold in rats and FGF19 rose 16-fold in rabbits associated with 62 and 75% reduction of CYP7A1 mRNA, respectively. Neither FGF15 nor FGF19 protein levels changed in the portal blood to correspond with the marked increase of FGF15/19 mRNA levels in the ileum or inhibited CYP7A1 expression in the liver. Further, in Ch-fed rats, CYP7A1 mRNA increased 1.9-fold (P < 0.001) although FGF15 mRNA levels in the ileum and portal blood FGF15 protein levels were not decreased. In Ch-fed rabbits, although FGF19 mRNA levels in the ileum and liver did not increase significantly, CYP7A1 mRNA declined 49% (P < 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.
有人提出，胆汁酸抑制 CYP7A1 基因表达是通过肠道-肝脏信号通路成纤维细胞生长因子 (FGF)15/19-成纤维细胞生长因子受体 4 介导的，该通路由回肠中法尼酯 X 受体的激活启动，但在肝脏中则不会。本研究评估了门静脉血液中的 FGF15/19 蛋白水平是否反映了回肠中 FGF15/19 mRNA 的变化。该研究在给予常规饮食（对照）的 Sprague Dawley 大鼠和新西兰白兔中进行，这些动物补充了胆固醇（Ch）或胆酸（CA）。给予 CA 后，大鼠回肠 FGF15 mRNA 增加了 8.5 倍，兔子 FGF19 增加了 16 倍，分别导致 CYP7A1 mRNA 减少 62%和 75%。门静脉血液中的 FGF15 或 FGF19 蛋白水平均未发生变化，与回肠中 FGF15/19 mRNA 水平的显著增加或肝脏中 CYP7A1 表达的抑制不一致。此外，在给予 Ch 的大鼠中，尽管 CYP7A1 mRNA 增加了 1.9 倍（P < 0.001），但回肠中 FGF15 mRNA 水平和门静脉血液中 FGF15 蛋白水平并未降低。在给予 Ch 的兔子中，尽管回肠和肝脏中 FGF19 mRNA 水平没有显著增加，但 CYP7A1 mRNA 下降了 49%（P < 0.05）。我们未能在大鼠和兔子中发现门静脉血液中 FGF15/19 蛋白水平的相应变化，在这些动物中，回肠中的 FGF15/19 mRNA 水平和肝脏中的 CYP7A1 mRNA 水平均发生了显著变化。
