Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling
Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling
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自分泌CTHRC1 通过激活TGF-β 信号激活肝星状细胞并促进肝纤维化。
DOI：
10.1016/j.ebiom.2019.01.009
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发表时间：
2019-02-01
期刊：
影响因子：
11.1
通讯作者：
Zhang, Zhigang
中科院分区：
文献类型：
--
作者：
Li, Jun;Wang, Yahui;Zhang, Zhigang
背景：肝纤维化是由慢性肝损伤引起的，可向肝硬化发展，甚至发展为肝细胞癌。然而，目前的治疗并不令人满意。方法：采用四氯化碳（CCl 4）或硫代乙酰胺（TAA）诱导野生型（WT）或CTHRC 1（-/-）小鼠肝纤维化模型，采用免疫荧光和免疫组织化学方法检测肝纤维化的发生、发展和转归。CTHRC 1单克隆抗体（mAb）被用来消除CTHRC 1的影响，在体外和在vivo.Results：在这里，我们报道了胶原三螺旋重复包含1（CTHRC 1），肝星状细胞（HSC）的分泌蛋白，在肝纤维化组织中显着上调。CTHRC 1可促进HSC从静止状态向活化状态转化，并通过激活TGF-β信号增强HSC的迁移或收缩能力。CTHRC 1竞争性结合Wnt受体，促进HSC的收缩，但不激活HSC。与同窝对照组相比，CCl 4或TAA诱导的CTHRC-/-小鼠肝纤维化减弱，而CTHRC 1的单克隆抗体抑制了用CCl 4或TAA.Interpretation处理的WT小鼠的肝纤维化：我们证明了CTHRC 1是通过调节TGF-β信号传导的肝纤维化的新调节剂。靶向CTHRC 1可能是一种很有前途的治疗方法，它可以抑制TGF-β信号传导，避免直接靶向TGF-β引起的副作用。CTHRC 1也可能是监测抗纤维化治疗反应的潜在生物标志物。(c)2019年，任作家。由爱思唯尔公司出版
Background: Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response.Methods: Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1(-/-) mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo.Results: Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-beta signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC-/- mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis inWT mice treated with CCl4 or TAA.Interpretation: We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-beta signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-beta signaling and avoid the side effects caused by directly targeting TGF-beta. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. (c) 2019 The Authors. Published by Elsevier B.V.