Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
Endoscopy Unit, Ministry of Internal Affairs Hospital, Szczecin, Poland.
Sci Rep. 2016 Dec 23;6:39573. doi: 10.1038/srep39573.
Pathogenesis of primary sclerosing cholangitis (PSC) may involve impaired bile acid (BA) homeostasis. We analyzed expressions of factors mediating enterohepatic circulation of BA using ileal and colonic (ascending and sigmoid) biopsies obtained from patients with PSC with and without ulcerative colitis (UC) and explanted PSC livers. Two-fold increase of BA-activated farnesoid X receptor (FXR) protein levels were seen in ascending and sigmoid colon of PSC patients with correspondingly decreased apical sodium-dependent BA transporter (ASBT) gene expression. This was associated with increased OSTβ protein levels in each part of analyzed gut. An intestinal fibroblast growth factor (FGF19) protein expression was significantly enhanced in ascending colon. Despite increased hepatic nuclear receptors (FXR, CAR, SHP), and FGF19, neither CYP7A1 suppression nor CYP3A4 induction were observed. The lack of negative regulation of BA synthesis may be accountable for lower levels of cholesterol observed in PSC in comparison to primary biliary cholangitis (PBC). In conclusion, chronic cholestasis in PSC induces adaptive changes in expression of BA transporters and FXR in the intestine. However hepatic impairment of expected in chronic cholestasis downregulation of CYP7A1 and upregulation of CYP3A4 may promote BA-induced liver injury in PSC.
原发性硬化性胆管炎（PSC）的发病机制可能涉及胆汁酸（BA）稳态的受损。我们使用从患有 PSC 伴或不伴溃疡性结肠炎（UC）的患者和 PSC 肝移植中获得的回肠和结肠（升结肠和乙状结肠）活检组织分析了介导 BA 肠肝循环的因子的表达。在 PSC 患者的升结肠和乙状结肠中，BA 激活的法尼醇 X 受体（FXR）蛋白水平增加了两倍，相应的顶端钠依赖性 BA 转运蛋白（ASBT）基因表达减少。这与分析肠道各个部位的 OSTβ 蛋白水平增加有关。在升结肠中，肠成纤维细胞生长因子（FGF19）蛋白表达显著增强。尽管肝脏核受体（FXR、CAR、SHP）和 FGF19 增加，但未观察到 CYP7A1 抑制或 CYP3A4 诱导。与原发性胆汁性胆管炎（PBC）相比，PSC 中胆固醇水平较低可能是由于 BA 合成的负反馈调节缺失所致。总之，PSC 中的慢性胆汁淤积诱导肠内 BA 转运体和 FXR 的表达适应性改变。然而，在慢性胆汁淤积中预期的 CYP7A1 下调和 CYP3A4 上调可能会促进 PSC 中的 BA 诱导的肝损伤。
