Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis.
Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis.
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DOI：
10.1038/srep39573
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发表时间：
2016-12-23
影响因子：
4.6
通讯作者：
Milkiewicz P
中科院分区：
文献类型：
--
作者：
Milkiewicz M;Klak M;Kempinska-Podhorodecka A;Wiechowska-Kozlowska A;Urasinska E;Blatkiewicz M;Wunsch E;Elias E;Milkiewicz P
原发性硬化性胆管炎（PSC）的发病机制可能涉及胆汁酸（BA）稳态受损。我们分析了介导BA的肠肝循环的因素的表达，使用回肠和结肠（升结肠和乙状结肠）活检，从PSC患者和没有溃疡性结肠炎（UC）和PSC肝硬化。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，相应地降低了顶端钠依赖性BA转运蛋白（ASBT）基因表达。这与分析的肠道各部分中OSTβ蛋白水平增加有关。肠成纤维细胞生长因子（FGF19）蛋白的表达显着增强，在升结肠。尽管肝核受体（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中观察到的胆固醇水平较低可能是由于缺乏BA合成的负调控。总之，PSC慢性胆汁淤积诱导肠道BA转运体和FXR表达的适应性变化。然而，在慢性胆汁淤积中，肝损害是预期的，CYP7A1的下调和CYP3A4的上调可能促进BA诱导的PSC肝损伤。
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.
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影响因子：
--
作者：
Lee, Youn-Kyoung;Schmidt, Daniel R.;Kliewer, Steven A.
通讯作者：
Kliewer, Steven A.
DOI：
10.1111/liv.12680
发表时间：
2015-01
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
Bell LN;Wulff J;Comerford M;Vuppalanchi R;Chalasani N
通讯作者：
Chalasani N
影响因子：
29.4
作者：
Modica, Salvatore;Petruzzelli, Michele;Moschetta, Antonio
通讯作者：
Moschetta, Antonio
DOI：
10.1152/ajpgi.00539.2005
发表时间：
2006-06-01
影响因子：
4.5
作者：
Boyer, James L.;Trauner, Michael;Ballatori, Nazzareno
通讯作者：
Ballatori, Nazzareno
影响因子：
13.5
作者：
Kong, Bo;Wang, Li;Guo, Grace L.
通讯作者：
Guo, Grace L.