H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule.
H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule.
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DOI：
10.1002/hep.29209
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Song Y;Liu C;Liu X;Trottier J;Beaudoin M;Zhang L;Pope C;Peng G;Barbier O;Zhong X;Li L;Wang L
基于我们最近的发现，小鼠胆汁酸（BA）稳态的破坏导致肝脏lncRNA H19表达的诱导，我们试图阐明H19在胆汁淤滞性肝纤维化中的作用。肝脏过表达H19RNA增强了胆管结联（BDL）诱导的肝纤维化，并伴有血清ALT、AST、胆红素和BA水平升高。与无bdl小鼠相比，H19-BDL小鼠中与肝纤维化、炎症和胆道增生相关的多个基因增加，而与BA合成相关的基因减少。H19-BDL小鼠肝脏和脾脏中CD3+γδ+、IL-4和IL-17显著富集，产生CD4+和CD8+免疫细胞群。H19下调肝锌指e -box结合同源盒1 (ZEB1)，上调上皮细胞粘附分子（EpCAM）和SRY（性别决定区Y）-box 9 （SOX9）表达。在机制上，ZEB1抑制EpCAM启动子活性和基因转录。H19RNA通过与ZEB1蛋白相互作用，阻止ZEB1蛋白与EpCAM启动子结合，从而阻碍ZEB1的抑制作用。肝脏过表达ZEB1或敲低EpCAM可减少h19诱导的纤维化；后者在H19−/−小鼠中也被阻止。胆汁酸在小鼠小胆管细胞（MSC）中显著诱导H19RNA，在小鼠大胆管细胞（MLC）中诱导程度较低。原发性硬化性胆管炎（PSC）和原发性胆汁性肝硬化（PBC）肝脏标本中，H19RNA和EpCAM的上调与ZEB1的下调呈正相关。结论：肝脏H19RNA的激活通过ZEB1/EpCAM信号通路促进小鼠胆汁淤积性肝纤维化。
Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic lncRNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum ALT, AST, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL vs Null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, IL-4, and IL-17 producing CD4+ and CD8+ immune cell populations. H19 downregulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but upregulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 (SOX9) expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1’s inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19−/− mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes (MSC) and to a lesser extent in mouse large cholangiocytes (MLC). The upregulation of H19RNA and EpCAM correlated positively with the downregulation of ZEB1 in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) liver specimens. Conclusions: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway.
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影响因子：
25.7
作者：
Mani SK;Zhang H;Diab A;Pascuzzi PE;Lefrançois L;Fares N;Bancel B;Merle P;Andrisani O
通讯作者：
Andrisani O
影响因子：
3.6
作者：
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通讯作者：
Forouhar F
DOI：
10.1152/ajpgi.00069.2014
发表时间：
2015-02-15
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Dollé L;Theise ND;Schmelzer E;Boulter L;Gires O;van Grunsven LA
通讯作者：
van Grunsven LA
影响因子：
64.8
作者：
Venkatraman, Aparna;He, Xi C.;Thorvaldsen, Joanne L.;Sugimura, Ryohichi;Perry, John M.;Tao, Fang;Zhao, Meng;Christenson, Matthew K.;Sanchez, Rebeca;Yu, Jaclyn Y.;Peng, Lai;Haug, Jeffrey S.;Paulson, Ariel;Li, Hua;Zhong, Xiao-bo;Clemens, Thomas L.;Bartolomei, Marisa S.;Li, Linheng
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Li, Linheng
影响因子：
29.4
作者：
Tsuchiya H;da Costa KA;Lee S;Renga B;Jaeschke H;Yang Z;Orena SJ;Goedken MJ;Zhang Y;Kong B;Lebofsky M;Rudraiah S;Smalling R;Guo G;Fiorucci S;Zeisel SH;Wang L
通讯作者：
Wang L