Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas
Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas
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DOI：
10.1016/s0016-5085(99)70461-0
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发表时间：
1999-09-01
期刊：
影响因子：
29.4
通讯作者：
Gores, GJ
中科院分区：
文献类型：
--
作者：
Miyoshi, H;Rust, C;Gores, GJ
背景和目的：胆汁淤积性肝损伤是由于有毒胆汁盐在肝内蓄积所致。有毒胆盐诱导的体外肝细胞凋亡是 Fas 依赖性的。本研究的目的是确定胆汁淤积期间体内肝细胞凋亡是否依赖于 Fas。方法：在胆管结扎 (BDL) Fas 缺陷 Ipr（淋巴增殖）小鼠和野生型小鼠中进行研究。结果：通过末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记和台盼蓝测定来定量细胞凋亡和坏死，确定肝细胞凋亡是细胞死亡的主要机制。肝细胞凋亡的机制取决于Fas受体的存在与否以及BDL的持续时间。持续 3 天的 BDL 后，仅野生型小鼠肝细胞凋亡增加，而 Ipr 小鼠则没有，表明细胞凋亡是 Fas 依赖性的。相反，在 BDL 大于或等于 7 天后，Ipr 动物中也发生肝细胞凋亡，这与 Fas 独立的细胞凋亡机制一致。 BDL Ipr 小鼠的肝细胞凋亡与 Bax 表达的增加以及 Bax 与线粒体的关联有关。结论：肝外胆汁淤积时，肝细胞凋亡是由Fas介导的。然而，在缺乏 Fas 受体的情况下，会发生肝细胞凋亡的其他机制。抑制多种细胞凋亡途径对于减轻慢性胆汁淤积性肝损伤是必要的。
Background & Aims: Cholestatic liver injury results from the intrahepatic accumulation of toxic bile salts. Toxic bile salt-induced hepatocyte apoptosis in vitro is Fas dependent. The aim of this study was to ascertain if hepatocyte apoptosis in vivo during cholestasis is Fas dependent. Methods: Studies were performed in bile duct-ligated (BDL) Fas-deficient Ipr (lymphoproliferation) and wild-type mice. Results: Hepatocyte apoptosis was the predominant mechanism of cell death as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and trypan blue assays to quantitate apoptosis and necrosis. The mechanisms of hepatocyte apoptosis were dependent on the presence or absence of the Fas receptor and the duration of BDL. After BDL of 3 days' duration, increased hepatocyte apoptosis occurred only in wild-type but not Ipr mice, indicating the apoptosis was Fas dependent. In contrast, after BDL of greater than or equal to 7 days, hepatocyte apoptosis also occurred in Ipr animals consistent with a Fas-independent mechanism of apoptosis. Hepatocyte apoptosis in BDL Ipr mice was associated with an increase in Bax expression and Bax association with mitochondria. Conclusions: During extrahepatic cholestasis, hepatocyte apoptosis is mediated by Fas. However, in the absence of the Fas receptor, additional mechanisms of hepatocyte apoptosis occur. Inhibition of multiple apoptotic pathways is necessary to attenuate chronic cholestatic liver injury.