CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
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DOI：
10.1152/ajpgi.00482.2007
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发表时间：
2008-02-01
影响因子：
4.5
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
--
作者：
Tamaki, Nobuyuki;Hatano, Etsuro;Uemoto, Shinji
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。该研究的目的是调查 CHOP 在胆汁淤积性肝损伤中的作用。在胆管结扎 (BDL) 后对野生型 (WT) 和 CHOP 缺陷小鼠的急性肝损伤和肝纤维化进行评估。在 WT 肝脏中，BDL 诱导 CHOP 和 Bax 过度表达，Bax 是 CHOP 介导的 ER 应激途径的下游靶标。 CHOP 敲除小鼠的肝纤维化减弱。在 CHOP 缺陷小鼠中，α-平滑肌肌动蛋白和转化生长因子-β 1 的表达水平降低，细胞凋亡和坏死性肝细胞死亡均减弱。从 WT 和 CHOP 缺陷小鼠中分离肝细胞，并用 400 μM 甘鹅去氧胆酸 (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 WT 肝细胞中 CHOP 和 Bax 的过度表达，而 CHOP 缺陷的肝细胞在 GCDCA 处理后减少了 caspase-3 的表达，并降低了碘化丙啶指数。总之，胆汁淤积会诱导 CHOP 介导的 ER 应激并引发肝细胞死亡，而 CHOP 缺乏会减弱这种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发挥重要作用。
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-beta 1 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 mu M 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.