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首页> 外文期刊>American Journal of Physiology >CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
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CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury

机译：CHOP缺乏症通过减少肝细胞损伤来减轻胆汁淤积性肝纤维化

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摘要

First published January 3, 2008; doi:10.1152/ajpgi.00482.2007.-CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a key component in endoplasmic reticulum (ER) stress-mediated apoptosis. The goal of the study was to investigate the role of CHOP in cholestatic liver injury. Acute liver injury and liver fibrosis were assessed in wild-type (WT) and CHOP-deficient mice following bile duct ligation (BDL). In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP-mediated ER stress pathway. Liver fibrosis was attenuated in CHOP-knockout mice. Expression levels of alpha-smooth muscle actin and transforming growth factor-pi were reduced, and apoptotic and necrotic hepatocyte death were both attenuated in CHOP-deficient mice. Hepatocytes were isolated from WT and CHOP-deficient mice and treated with 400 muM glycochenodeoxycholic acid (GCDCA) for 8 h to examine bile acid-induced apoptosis and necrosis. GCDCA induced overexpression of CHOP and Bax in isolated WT hepatocytes, whereas CHOP-deficient hepatocytes had reduced cleaved caspase-3 expression and a lower propidium iodide index after GCDCA treatment. In conclusion, cholestasis induces CHOP-mediated ER stress and triggers hepatocyte cell death, and CHOP deficiency attenuates this cell death and subsequent liver fibrosis. The results demonstrate an essential role of CHOP in development of liver fibrosis due to cholestatic liver damage.
机译：2008年1月3日首次发布; doi：10.1152 / ajpgi.00482.2007.-CCAAT /增强子结合蛋白（C / EBP）同源蛋白（CHOP）是内质网（ER）应激介导的细胞凋亡的关键成分。该研究的目的是研究CHOP在胆汁淤积性肝损伤中的作用。在胆管结扎（BDL）后，在野生型（WT）和CHOP缺陷型小鼠中评估了急性肝损伤和肝纤维化。在野生型肝中，BDL诱导了CHOP和Bax的过表达，而Bax是CHOP介导的ER应激途径的下游靶标。在CHOP基因敲除小鼠中肝纤维化减弱。在CHOP缺陷型小鼠中，α-平滑肌肌动蛋白和转化生长因子-pi的表达水平降低，凋亡和坏死性肝细胞死亡均减弱。从WT和CHOP缺陷型小鼠分离肝细胞，并用400μM糖去氧胆酸（GCDCA）处理8小时，以检查胆汁酸诱导的细胞凋亡和坏死。 GCDCA诱导分离的野生型肝细胞中CHOP和Bax的过表达，而GCDCA处理后，CHOP缺陷型肝细胞具有降低的caspase-3裂解表达和较低的碘化丙啶指数。总之，胆汁淤积会诱发CHOP介导的内质网应激，并触发肝细胞死亡，而CHOP缺乏则减弱该细胞死亡和随后的肝纤维化。结果表明，CHOP在胆汁淤积性肝损伤引起的肝纤维化发展中起着至关重要的作用。

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