Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice.
Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice.
复制标题
DOI：
10.1038/labinvest.2016.112
复制
发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
胆汁淤积是一种导致慢性肝胆炎症、纤维化和最终肝硬化的病症。已知许多microRNA（miR）在纤维化进展中起作用;然而，miR-21在胆汁淤积期间的作用仍然未知。因此，本研究的目的是阐明miR-21在胆汁淤积诱导的胆管增生和肝纤维化中的作用。野生型（WT）和miR 21 −/−小鼠进行假手术或胆管结扎（BDL）1周，然后评价肝脏组织学、胆管增殖、肝星状细胞（HSC）活化、纤维化反应和Smad-7表达。在体外，在分析增殖、凋亡和纤维化反应之前，用miR-21抑制剂或对照处理永生化鼠胆管细胞系（IMCL）和人肝星状细胞系（hHSC）。在体内，BDL后总肝脏和胆管细胞中的miR-21水平增加，miR-21的缺失降低了BDL诱导的胆管增殖和肝内胆管质量的量。此外，miR-21的缺失降低了BDL诱导的HSC活化、胶原沉积以及纤维化标志物TGF-β1和α-SMA的表达。在体外，与对照处理的细胞相比，用miR-21抑制剂处理的IMCL和hHSC显示出降低的增殖和纤维化标志物表达以及增强的凋亡。此外，缺乏miR-21的小鼠显示Smad-7表达增加，这可能是驱动胆管增生和肝纤维化减少的原因。在胆汁淤积性损伤期间，miR-21增加并导致胆汁增殖和肝纤维化增加。局部调节miR-21可能是胆汁淤积患者的一种治疗选择。
Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR21−/− mice underwent sham or bile duct ligation (BDL) for 1 wk, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and Smad-7 expression. In vitro, immortalized murine biliary cell lines (IMCL) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. Also, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers TGF-β1 and α-SMA. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared to control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.
登录
查看更多内容
DOI：
10.1038/labinvest.2009.6
发表时间：
2009-04
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
姜黄素通过抑制胆管细胞炎症反应和门户肌纤维细胞增殖来改善MDR2 - / - 小鼠中的硬化性胆管炎。
影响因子：
24.5
作者：
Baghdasaryan A;Claudel T;Kosters A;Gumhold J;Silbert D;Thüringer A;Leski K;Fickert P;Karpen SJ;Trauner M
通讯作者：
Trauner M
影响因子：
5
作者：
Kinnman, N;Goria, O;Housset, C
通讯作者：
Housset, C
影响因子：
5
作者：
Kennedy, Lindsey L.;Hargrove, Laura A.;Francis, Heather L.
通讯作者：
Francis, Heather L.
DOI：
10.1016/j.trsl.2011.01.008
发表时间：
2011-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Kerr TA;Korenblat KM;Davidson NO
通讯作者：
Davidson NO