Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells.
Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells.
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DOI：
10.1155/2016/7478650
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发表时间：
2016
影响因子：
--
通讯作者：
Ming X
中科院分区：
文献类型：
--
作者：
Wu L;Mao C;Ming X
由于慢性病毒性肝炎以及最近的脂肪肝疾病，肝纤维化是全世界发病率和死亡率的主要原因。肝星状细胞（HSC）的活化和增殖是肝纤维化的一个重要方面，并与HSC凋亡的进行性减少有关。Bcl-x是Bcl-2基因家族中的抗凋亡基因，在哺乳动物细胞凋亡调控中起重要作用。通过选择性剪接，Bcl-x基因产生具有相反功能的两种主要蛋白质同种型，抗凋亡Bcl-xL和促凋亡Bcl-xS。本研究旨在探讨Bcl-x及其选择性剪接在肝星状细胞凋亡中的作用。结果表明，Bcl-xL在活化的人HSC中的表达明显高于Bcl-2。当HSC在细胞培养中被激活时，Bcl-xL相对于Bcl-xS的相对表达逐渐增加，这与激活的HSC的凋亡抵抗性增加一致。通过反义寡核苷酸将Bcl-x剪接从抗凋亡异构体重定向为促凋亡异构体诱导HSC死亡，而无需其他凋亡刺激。结论Bcl-x在肝星状细胞凋亡的调控中起重要作用，调控Bcl-x选择性剪接可能成为治疗肝纤维化的一种新的分子治疗手段。
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver diseases. Activation and proliferation of hepatic stellate cells (HSCs) represent a key aspect of fibrogenesis and are associated with progressive reduction of HSC apoptosis. Bcl-x, an antiapoptotic member of Bcl-2 gene family, plays a role in apoptosis regulation in mammalian cells. Through alternative splicing, the Bcl-x gene yields two major protein isoforms with opposing functions, antiapoptotic Bcl-xL and proapoptotic Bcl-xS. This study aimed to investigate the role of Bcl-x and its alternate splicing in HSC apoptosis. The results indicated that the expression of Bcl-xL was dramatically higher than Bcl-2 in activated human HSCs. The relative expression of Bcl-xL over Bcl-xS increased gradually when HSCs were activated in cell culture, which was consistent with the increase in apoptosis resistance of activated HSCs. Redirection of Bcl-x splicing by an antisense oligonucleotide from the antiapoptotic isoform to the proapoptotic isoform induced death of HSCs without other apoptosis stimuli. We conclude that Bcl-x plays a role in regulation of HSC apoptosis and modulation of Bcl-x alternative splicing may become a novel molecular therapy for liver fibrosis.