Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses
Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses
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DOI：
10.1053/j.gastro.2004.07.019
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发表时间：
2004-10-01
期刊：
影响因子：
29.4
通讯作者：
Hayashi, N
中科院分区：
文献类型：
--
作者：
Takehara, T;Tatsumi, T;Hayashi, N
背景和目标：最近的研究表明，细胞凋亡可能参与纤维化的发展，尽管它通常被认为是一种细胞去除机制，而不会对组织产生影响。Bcl-2家族的抗凋亡成员Bcl-x（L）在肝细胞中表达，并在各种病理条件下上调。本研究的目的是利用Cre-loxP系统探讨Bcl-x（L）在肝细胞中的功能，并分析肝细胞长期凋亡的后果。研究方法：用表达Cre重组酶基因（AdexCre）的重组腺病毒感染从floxed bcl-x等位基因（bcl-x fl/fl）纯合子小鼠中分离的肝细胞。将Bcl-x fl/fl小鼠与在白蛋白基因启动子调控下表达Cre的Alb-Cre转基因小鼠杂交以产生肝细胞特异性Bcl-x（L）缺陷小鼠。结果如下：在AdexCre感染时，原代培养的bcl-x fl/fl肝细胞减少其Bcl-x（L）的表达，并迅速经历与线粒体损伤相关的凋亡。体内肝细胞特异性破坏Bcl-x（L）导致肝细胞自发凋亡超过6个月。Bcl-x（L-）缺陷小鼠表现出肝纤维化与先进的年龄，这是之前的肝转化生长因子β生产的增加。在体外，巨噬细胞和肝细胞在暴露于凋亡肝细胞时产生转化生长因子β。结论：Bcl-x（L）是一种重要的肝细胞凋亡拮抗剂。此外，它提供了实质细胞的持续凋亡足以诱导纤维化反应的证据，并表明凋亡和纤维化之间的机制联系。
Background & Aims: Recent research has suggested that apoptosis could be involved in the development of fibrosis, although it is generally considered to be a mechanism of cell removal without consequences to the tissue. Bcl-x(L), an antiapoptotic member of the Bcl-2 family, is expressed in hepatocytes and up-modulated during various pathologic conditions. The aim of this study was to explore the function of Bcl-x(L) in hepatocytes using the Cre-loxP system and to analyze the consequences of long-term apoptosis in hepatocytes. Methods: Hepatocytes isolated from mice homozygous for a floxed bcl-x allele (bcl-x fl/fl) were infected with recombinant adenovirus expressing the Cre recombinase gene (AdexCre). Bcl-x fl/fl mice were crossed with Alb-Cre transgenic mice, which express Cre under regulation of the albumin gene promoter to generate hepatocyte-specific Bcl-x(L)-deficient mice. Results: On AdexCre infection, primary cultured bcl-x fl/fl hepatocytes reduced their expression of Bcl-x(L) and rapidly underwent apoptosis associated with mitochondrial damage. In vivo hepatocyte-specific disruption of Bcl-x(L) resulted in spontaneous apoptosis of hepatocytes for more than 6 months. The Bcl-x(L-) deficient mice showed liver fibrosis with advanced age that was preceded by an increase in hepatic transforming growth factor beta production. In vitro, macrophages and hepatocytes produced transforming growth factor beta on exposure to apoptotic hepatocytes. Conclusions: The present study identified Bcl-x(L) as a critical apoptosis antagonist in hepatocytes. Furthermore, it offers proof that persistent apoptosis of parenchymal cells is sufficient to induce fibrotic responses and suggests a mechanistic link between apoptosis and fibrosis.