Human antigen R contributes to hepatic stellate cell activation and liver fibrosis.
Human antigen R contributes to hepatic stellate cell activation and liver fibrosis.
复制标题
DOI：
10.1002/hep.25828
复制
发表时间：
2012-11
期刊：
影响因子：
13.5
通讯作者：
Martinez-Chantar, Maria L.
中科院分区：
文献类型：
--
作者：
Woodhoo, Ashwin;Iruarrizaga-Lejarreta, Marta;Beraza, Naiara;Garcia-Rodriguez, Juan L.;Embade, Nieves;Fernandez-Ramos, David;Martinez-Lopez, Nuria;Gutierrez-De Juan, Virginia;Arteta, Beatriz;Caballeria, Juan;Lu, Shelly C.;Mato, Jose M.;Varela-Rey, Marta;Martinez-Chantar, Maria L.
RNA结合蛋白(RBPs)在控制mRNA周转和翻译速率方面起着重要作用。我们研究了RBP人类抗原R(HUR)在淤胆性肝损伤和肝星状细胞(HSC)激活中的作用。HUR沉默减轻了BDL后体内纤维化的发展，减少了肝损伤、氧化应激、炎症、胶原和α-SMA(α-平滑肌肌动蛋白)的表达。Hur在BDL小鼠活化的HSC和体外激活的HSC中的表达增加，而Hur的沉默显著降低HSC的激活。HUR调控血小板衍生生长因子(PDGF)诱导的增殖和迁移，并控制参与这些过程的几个mRNAs的表达(肌动蛋白、MMP9、Cyclin D1和B1)。HUR的这些功能与其丰度和胞浆定位有关，分别通过ERK和PI3K激活以及ERK-LKB1激活受PDGF控制。更重要的是，我们发现肿瘤抑制基因LKB1是PDGF诱导HSC ERK激活的新下游靶点。HUR还通过调节转化生长因子-β-β，α-SMA和p21的表达来控制转化生长因子-β(转化生长因子-β)诱导的促纤维化作用。这可能是由于HUR的细胞质定位增加，受转化生长因子-β诱导的p38MAPK激活控制。最后，我们发现HUR和LKB1(Ser428)在人的肝硬变样本中的活化HSC中高表达。结论：HUR在胆汁淤积性肝损伤模型肝纤维化的发生发展、肝星状细胞的激活以及活化的肝星状细胞对血小板衍生生长因子和转化生长因子-β的反应中起重要作用。
RNA-binding proteins (RBPs) play a major role in control of mRNA turnover and translation rates. We examined the role of the RBP human antigen R (HuR) during cholestatic liver injury and hepatic stellate cells (HSC) activation. HuR silencing attenuated fibrosis development in vivo after BDL, reducing liver damage, oxidative stress, inflammation, and collagen and α-SMA (α-smooth muscle actin) expression. HuR expression increased in activated HSC from BDL mice and during HSC activation in vitro, and HuR silencing markedly reduced HSC activation. HuR regulated platelet-derived growth factor (PDGF)-induced proliferation and migration, and controlled expression of several mRNAs involved in these processes (Actin, MMP9, Cyclin D1 and B1). These functions of HuR were linked to its abundance and cytoplasmic localisation, controlled by PDGF, via ERK and PI3K activation, and ERK-LKB1 activation respectively. More importantly, we identified the tumor suppressor LKB1 as a novel downstream target of PDGF-induced ERK activation in HSC. HuR also controlled transforming growth factor beta (TGF-β-induced profibrogenic actions by regulating expression of TGF-β, α-SMA, and p21. This was likely due to an increased cytoplasmic localisation of HuR, controlled by TGF-β-induced p38 MAPK activation. Finally, we found that HuR and LKB1 (Ser428) levels were highly expressed in activated HSC in human cirrhotic samples. Conclusion: Our results show that HuR is important for pathogenesis of liver fibrosis development in the cholestatic injury model, for HSC activation, and for the response of activated HSC to PDGF and TGF-β.
登录
查看更多内容
影响因子：
5
作者：
Borkham-Kamphorst, E;Herrmann, J;Weiskirchen, R
通讯作者：
Weiskirchen, R
影响因子：
29.4
作者：
Martinez-Chantar, Maria L.;Vazquez-Chantada, Mercedes;Mato, Jose M.
通讯作者：
Mato, Jose M.
影响因子：
29.4
作者：
Marra, F;Gentilini, A;Gentilini, P
通讯作者：
Gentilini, P
影响因子：
4.8
作者：
Krishnamurthy, Prasanna;Lambers, Erin;Kishore, Raj
通讯作者：
Kishore, Raj
影响因子：
4.6
作者：
Carotti, Simone;Morini, Sergio;Gaudio, Eugenio
通讯作者：
Gaudio, Eugenio