Knockdown of N-Acetylglucosaminyl Transferase V Ameliorates Hepatotoxin-Induced Liver Fibrosis in Mice
Knockdown of N-Acetylglucosaminyl Transferase V Ameliorates Hepatotoxin-Induced Liver Fibrosis in Mice
复制标题
N-乙酰氨基葡萄糖转移酶 V 的敲低可改善肝毒素诱导的小鼠肝纤维化。
DOI：
10.1093/toxsci/kft135
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发表时间：
2013-09-01
影响因子：
3.8
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
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作者：
Liu, Junyu;Zhang, Zhengping;Zhang, Junfeng
N-乙酰氨基葡萄糖转移酶 V (GnT-V) 表达改变引起的异常 N-糖基化已知可通过调节多种细胞因子信号通路来调节肿瘤侵袭和转移。然而，GnT-V 在肝纤维化发展中的确切作用尚未明确。在这里，我们通过腹腔注射四氯化碳（CCl4）或硫代乙酰胺（TAA）诱导小鼠肝纤维化，并观察到肝纤维化过程中肝脏GnT-V显着增加。同时，在活化的肝星状细胞（HSC）和受损的肝细胞中检测到 GnT-V 的上调。为了降低肝脏 GnT-V 的表达，通过尾静脉注射表达 GnT-V siRNA 的腺病毒。腺病毒介导的 GnT-V siRNA 递送显着降低了纤维化肝脏中的 GnT-V 表达并激活了体内 HSC，从而减轻了 CCl4 或 TAA 诱导的肝纤维化（通过胶原蛋白沉积和促纤维化标记物概况进行评估）。此外，HSC 中 GnT-V 的敲低会减少转化生长因子 β (TGF-)/Smad 信号传导，并削弱激活的 HSC 表型。 HSC 中 TGF-/Smad 信号传导的抑制与 TGF-受体上 GnT-V 修饰的 1,6-支链 N-聚糖的减少相关。 GnT-V 的敲低还通过抑制 PDGF/Erk 信号传导来抑制血小板衍生生长因子 (PDGF) 诱导的 HSC 增殖和迁移。最后，我们通过形态学评估和 EMT 标记物的逆转证明，GnT-V 的敲低可显着抑制 TGF-1 诱导的肝细胞上皮间质转化 (EMT)。总之，本研究表明 GnT-V 与肝毒素诱导的肝纤维化有关，靶向 GnT-V 可能是治疗肝纤维化的可行且有前景的方法。
Aberrant N-glycosylation caused by altered N-acetyl glucosaminyltransferase V (GnT-V) expression is known to regulate tumor invasion and metastasis by modulating multiple cytokine signaling pathways. However, the exact role of GnT-V in the development of liver fibrosis has not been clearly defined. Here, we induced mouse liver fibrosis by ip injections of carbon tetrachloride (CCl4) or thioacetamide (TAA) and observed significant increase of hepatic GnT-V during the processes of liver fibrogenesis. Meanwhile, upregulations of GnT-V were detected in the activated hepatic stellate cells (HSCs) and injured hepatocytes. To knock down hepatic GnT-V expression, adenovirus that expressed the GnT-V siRNA was injected via the tail vein. Adenovirus-mediated delivery of GnT-V siRNA dramatically reduced the GnT-V expression in fibrotic liver and activated HSC in vivo and consequently alleviated CCl4- or TAA-induced liver fibrosis as assessed through collagen deposition and profiles of profibrogenic markers. Furthermore, knockdown of GnT-V in HSCs reduced transforming growth factor beta (TGF-)/Smad signaling and blunted the activated HSC phenotype. The suppression of TGF-/Smad signaling in HSCs correlated with the decrease of GnT-V-modified 1,6-branched N-glycan on TGF- receptors. Knockdown of GnT-V also suppressed platelet-derived growth factor (PDGF)induced HSC proliferation and migration through inhibiting PDGF/Erk signaling. Finally, we demonstrated that knockdown of GnT-V profoundly suppressed TGF-1-induced epithelial-mesenchymal transition (EMT) in hepatocytes by morphological assessment and reversal of EMT markers. In conclusion, this study demonstrates that GnT-V is implicated in hepatotoxin-induced liver fibrosis, and targeting GnT-V may be a feasible and promising approach for treating liver fibrosis.