Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction.
Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction.
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胆石性胆道梗阻引起的人类梗阻性胆汁淤积中肝脏解毒酶的表达减少
DOI：
10.1371/journal.pone.0120055
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Chai J;Feng X;Zhang L;Chen S;Cheng Y;He X;Yang Y;He Y;Wang H;Wang R;Chen W
背景与目的胆汁酸代谢酶和膜转运蛋白的水平在胆汁淤积中发生变化。这些改变（例如CYP 7A 1抑制和MRP 4诱导）被认为是减轻胆汁淤积性肝损伤的适应性反应。然而，这些适应性反应的分子机制在人类阻塞性胆汁淤积由于胆结石胆道梗阻仍然不清楚。方法我们收集了因胆结石引起的胆汁淤积性胆道梗阻患者和对照组无肝病患者的肝脏样本（每组n = 22）。胆汁酸合成和解毒酶，膜转运蛋白，以及相关的核受体和转录因子的表达水平进行了测定。结果胆汁淤积性肝胆汁酸合成酶CYP 7 B1、CYP 8B 1和解毒酶CYP 2B 6分别升高2.4倍、2.8倍和1.9倍（p<0.05）。相反，肝解毒酶UGT 2B 4/7、SULT 2A 1、GSTA 1 -4和GSTM 1 -4的表达水平在人阻塞性胆汁淤积中降低约50%（p<0.05）。在人胆汁淤积性肝脏中，膜转运蛋白OSTβ和OCT 1的水平分别增加10.4倍和1.8倍（p<0.05），而OSTα、ABCG 2和ABCG 8的水平均下降约40%（p<0.05）。在人阻塞性胆汁淤积症中，肝核受体VDR、HNF 4 α、RXRα和RARα被诱导（约2.0倍，p<0.05），而FXR水平显著降低至对照组的44%（p<0.05）。梗阻性胆汁淤积患者肝组织FXR mRNA表达水平与UGT 2B 4/7、SULT 2A 1、GSTA 1、ABCG 2/8 mRNA表达水平呈显著正相关（p<0.05）。结论阻塞性胆汁淤积症患者肝脏解毒酶水平显著降低，且与FXR水平显著降低呈正相关。这些发现与人类阻塞性胆汁淤积症的解毒能力受损一致。
Background & Aims Levels of bile acid metabolic enzymes and membrane transporters have been reported to change in cholestasis. These alterations (e.g. CYP7A1 repression and MRP4 induction) are thought to be adaptive responses that attenuate cholestatic liver injury. However, the molecular mechanisms of these adaptive responses in human obstructive cholestasis due to gallstone biliary obstruction remain unclear. Methods We collected liver samples from cholestatic patients with biliary obstruction due to gallstones and from control patients without liver disease (n = 22 per group). The expression levels of bile acid synthetic and detoxification enzymes, membrane transporters, and the related nuclear receptors and transcriptional factors were measured. Results The levels of bile acid synthetic enzymes, CYP7B1 and CYP8B1, and the detoxification enzyme CYP2B6 were increased in cholestatic livers by 2.4-fold, 2.8-fold, and 1.9-fold, respectively (p<0.05). Conversely, the expression levels of liver detoxification enzymes, UGT2B4/7, SULT2A1, GSTA1-4, and GSTM1-4, were reduced by approximately 50% (p<0.05) in human obstructive cholestasis. The levels of membrane transporters, OSTβ and OCT1, were increased 10.4-fold and 1.8-fold, respectively, (p<0.05), whereas those of OSTα, ABCG2 and ABCG8 were all decreased by approximately 40%, (p<0.05) in human cholestatic livers. Hepatic nuclear receptors, VDR, HNF4α, RXRα and RARα, were induced (approximately 2.0-fold, (p<0.05) whereas FXR levels were markedly reduced to 44% of control, (p<0.05) in human obstructive cholestasis. There was a significantly positive correlation between the reduction in FXR mRNA and UGT2B4/7, SULT2A1, GSTA1, ABCG2/8 mRNA levels in livers of obstructive cholestatic patients (p<0.05). Conclusions The levels of hepatic detoxification enzymes were significantly decreased in human obstructive cholestasis, and these decreases were positively associated with a marked reduction of FXR levels. These findings are consistent with impaired detoxification ability in human obstructive cholestasis.
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人梗阻性胆汁淤积中肝多药耐药相关蛋白 3/ATP 结合盒亚家族 C 3 表达升高是通过肿瘤坏死因子 α 和 c-Jun NH2 末端激酶/应激激活蛋白激酶信号通路介导的。
影响因子：
13.5
作者：
Chai, Jin;He, Yu;Cai, Shi-Ying;Jiang, Zhongyong;Wang, Huaizhi;Li, Qiong;Chen, Lei;Peng, Zhihong;He, Xiaochong;Wu, Xiaoping;Xiao, Tianli;Wang, Rongquan;Boyer, James L.;Chen, Wensheng
通讯作者：
Chen, Wensheng
DOI：
10.1152/ajpgi.00191.2006
发表时间：
2007-05-01
影响因子：
4.5
作者：
Chen, Wensheng;Cai, Shi-Ying;Boyer, James L.
通讯作者：
Boyer, James L.
影响因子：
29.4
作者：
Boyer, JL
通讯作者：
Boyer, JL
影响因子：
13.5
作者：
Nies, Anne T.;Koepsell, Hermann;Schaeffeler, Elke
通讯作者：
Schaeffeler, Elke
影响因子：
29.4
作者：
Modica, Salvatore;Petruzzelli, Michele;Moschetta, Antonio
通讯作者：
Moschetta, Antonio