miR-15b and miR-16 regulate TNF mediated hepatocyte apoptosis via BCL2 in acute liver failure
miR-15b and miR-16 regulate TNF mediated hepatocyte apoptosis via BCL2 in acute liver failure
复制标题
miR-15b和miR-16在急性肝衰竭中通过BCL2调节TNF介导的肝细胞凋亡
DOI：
10.1007/s10495-012-0704-7
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发表时间：
2012-07-01
期刊：
影响因子：
7.2
通讯作者：
Xie, Qing
中科院分区：
文献类型：
--
作者：
An, Fangmei;Gong, Bangdong;Xie, Qing
急性肝衰竭（ALF）仍然有一个不可接受的高死亡率，尽管与多学科护理的实质性改善。ALF的确切潜在机制仍有待探索。已有报道microRNAs（miRNAs）是许多肝脏疾病的新型调控因子，但miRNAs在ALF发生发展中的作用尚未完全阐明。通过ip注射d-GalN/LPS建立ALF小鼠模型，其通过组织病理学和生物化学证实。采用基因芯片技术检测ALF中肝脏miRNA的表达谱，并通过qRT-PCR技术进行验证。通过生物信息学分析，预测这些去调控的miRNAs靶基因的功能和信号通路。通过探讨miRNA修饰与肝细胞凋亡的关系，探讨其可能的机制。ALF组与假手术组相比，共检测到95条差异有统计学意义的miRNA（P< 0.01）。在这95个miRNAs中，20个在5和7 h时间点上调，26个下调。生物信息学分析预测这46个miRNAs中的一些参与了细胞凋亡。在参与凋亡的上调miRNA中，miR-15 b和miR-16显示出最高的富集，并靶向共同的抗凋亡基因BCL 2。我们的体外实验数据表明，miR-15 b和/或miR-16在蛋白水平上调节BCL 2。抑制miR-15 b和/或miR-16可减少肝细胞凋亡和TNF产生。这些数据表明，miR-15 b和miR-16调节TNF介导的肝细胞凋亡通过BCL 2在ALF期间，并可能揭示了治疗ALF的治疗策略的发展。
Acute liver failure (ALF) still has an unacceptable high mortality rate, despite substantial improvements with multidisciplinary care. The precise underlying mechanism of ALF remains to be explored. It has been reported that microRNAs (miRNAs) are novel regulators in a number of liver diseases, but the role of miRNAs in the development of ALF is not fully understood. An ALF murine model was generated by ip injection ofd-GalN/LPS, which was confirmed with histopathology and biochemistry. The hepatic miRNA expression profile in ALF was determined by microarray and verified by qRT-PCR. The functions and signal pathways of the targeted genes of these deregulated miRNAs were predicted, using bioinformatics analysis. The possible underlying mechanism was investigated by exploring the relationship between miRNA modification and hepatocyte apoptosis. There were a total of 95 significantly changed miRNAs in ALF compared to mock-treated (P< 0.01). Among these 95 miRNAs, 20 were up-regulated and 26 were down-regulated at both 5 and 7 h time points. Bioinformatics analysis predicted that some of these 46 miRNAs were involved in apoptosis. Among the up-regulated miRNAs involved in apoptosis, miR-15b and miR-16 showed the highest enrichment and targeted the common anti-apoptotic gene, BCL2. Our in vitro data demonstrated that miR-15b and/or miR-16 regulated BCL2 at the protein level. Inhibition of miR-15b and/or miR-16 reduced hepatic apoptosis and TNF production. These data suggest that miR-15b and miR-16 regulate TNF mediated hepatic apoptosis via BCL2 during ALF, and may shed light on the development of a therapeutic strategy for treatment of ALF.