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缺乏 Nogo-B(reticulon 4B)可促进肝星状细胞凋亡,减少小鼠肝纤维化。

Absence of Nogo-B (reticulon 4B) facilitates hepatic stellate cell apoptosis and diminishes hepatic fibrosis in mice.

机构信息

Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

出版信息

Am J Pathol. 2013 Mar;182(3):786-95. doi: 10.1016/j.ajpath.2012.11.032. Epub 2013 Jan 9.

Abstract

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.

摘要

Nogo-B(网抑素 4B)加重肝纤维化和肝硬化,但机制尚不清楚。本研究旨在确定 Nogo-B 在肝星状细胞(HSC)凋亡在肝硬化中的作用。采用四氯化碳吸入法在野生型(WT)和 Nogo-A/B 敲除(Nogo-B KO)小鼠中诱导肝硬化。从 WT 和 Nogo-B KO 小鼠中分离 HSCs 并进行培养,以激活和转化为肌成纤维细胞(MF-HSCs)。使用人肝星状细胞(LX2 细胞)评估沉默或过表达 Nogo-B 后活化的 HSC 的凋亡反应。与 WT 小鼠相比,肝硬化 Nogo-B KO 小鼠的肝脏纤维化明显减少(P < 0.05)。在肝硬化 Nogo-B KO 肝脏的纤维化区域中,凋亡细胞更为明显。与 WT MF-HSCs 相比,Nogo-B KO MF-HSCs 在受到 staurosporine 刺激时,凋亡标志物 cleaved poly (ADP-ribose) polymerase 和 caspase-3 和 -8 的水平明显升高(P < 0.05)。用内质网应激诱导剂 tunicamycin 处理后,与 WT MF-HSCs 相比,Nogo-B KO MF-HSCs 中的 cleaved caspase-3 和 -8 水平升高(P < 0.01)。在 LX2 细胞中,Nogo-B 敲低增强了对 staurosporine 的凋亡反应,而 Nogo-B 过表达抑制了凋亡。实验性肝硬化中 HSC 中 Nogo-B 的缺失增强了凋亡。选择性阻断 HSCs 中的 Nogo-B 可能代表减轻肝纤维化的潜在治疗策略。

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