Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice.
Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice.
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DOI：
10.1016/j.ajpath.2012.11.032
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
K. Tashiro;Ayano Satoh;Teruo Utsumi;C. Chung;Y. Iwakiri
中科院分区：
文献类型：
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作者：
K. Tashiro;Ayano Satoh;Teruo Utsumi;C. Chung;Y. Iwakiri
Nogo-B（reticulon 4 B）加重肝纤维化和肝硬化，但机制尚不清楚。本研究的目的是确定Nogo-B在肝星状细胞（HSC）凋亡中的作用。通过在野生型（WT）和Nogo-A/B敲除（Nogo-B KO）小鼠中吸入四氯化碳产生肝硬化。从WT和Nogo-B KO小鼠中分离HSC，并培养用于活化和转化为肌成纤维细胞（MF-HSC）。使用人肝星状细胞（LX 2细胞）来评估在沉默或过表达Nogo-B后活化的HSC的凋亡应答。与WT小鼠相比，来自阿尔茨海默病Nogo-B KO小鼠的肝脏显示出显著减少的纤维化（P< 0.05）。凋亡细胞在坏死的Nogo-B KO肝脏的纤维化区域中更突出。与WT MF-HSC相比，Nogo-B KO MF-HSC显示响应于星形孢菌素的凋亡标志物、裂解的聚（ADP-核糖）聚合酶和半胱天冬酶-3和-8的水平显著增加（P< 0.05）。与WT MF-HSC相比，用内质网应激诱导剂衣霉素处理增加了Nogo-B KO MF-HSC中裂解的半胱天冬酶-3和-8水平（P< 0.01）。在LX 2细胞中，Nogo-B敲低增强了对星形孢菌素的响应的凋亡，而Nogo-B过表达抑制了凋亡。实验性肝硬化中Nogo-B的缺失增强了HSC的凋亡选择性阻断HSC中的Nogo-B可能代表减轻肝纤维化的潜在治疗策略。
Nogo-B (reticulon 4B) accentuates hepatic fibrosis and cirrhosis, but the mechanism remains unclear. The aim of this study was to identify the role of Nogo-B in hepatic stellate cell (HSC) apoptosis in cirrhotic livers. Cirrhosis was generated by carbon tetrachloride inhalation in wild-type (WT) and Nogo-A/B knockout (Nogo-B KO) mice. HSCs were isolated from WT and Nogo-B KO mice and cultured for activation and transformation to myofibroblasts (MF-HSCs). Human hepatic stellate cells (LX2 cells) were used to assess apoptotic responses of activated HSCs after silencing or overexpressing Nogo-B. Livers from cirrhotic Nogo-B KO mice showed significantly reduced fibrosis (P< 0.05) compared with WT mice. Apoptotic cells were more prominent in fibrotic areas of cirrhotic Nogo-B KO livers. Nogo-B KO MF-HSCs showed significantly increased levels of apoptotic markers, cleaved poly (ADP-ribose) polymerase, and caspase-3 and -8 (P< 0.05) compared with WT MF-HSCs in response to staurosporine. Treatment with tunicamycin, an endoplasmic reticulum stress inducer, increased cleaved caspase-3 and -8 levels in Nogo-B KO MF-HSCs compared with WT MF-HSCs (P< 0.01). In LX2 cells, Nogo-B knockdown enhanced apoptosis in response to staurosporine, whereas Nogo-B overexpression inhibited apoptosis. The absence of Nogo-B enhances apoptosis of HSCs in experimental cirrhosis. Selective blockade of Nogo-B in HSCs may represent a potential therapeutic strategy to mitigate liver fibrosis.