Loss of Histone Deacetylases 1 and 2 in Hepatocytes Impairs Murine Liver Regeneration Through Ki67 Depletion
Loss of Histone Deacetylases 1 and 2 in Hepatocytes Impairs Murine Liver Regeneration Through Ki67 Depletion
复制标题
肝细胞中组蛋白脱乙酰酶 1 和 2 的缺失会通过 Ki67 耗竭损害小鼠肝脏再生
DOI：
10.1002/hep.26542
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发表时间：
2013-12-01
期刊：
影响因子：
13.5
通讯作者：
Bu, Hong
中科院分区：
文献类型：
--
作者：
Xia, Jie;Zhou, Yongjie;Bu, Hong
组蛋白脱乙酰酶1和2(HDAC1和HDAC2)在包括肝脏在内的组织中广泛表达，并在许多生理病理过程中发挥关键作用。人们对HDAC1和HDAC2在肝脏再生中的作用知之甚少。在这项研究中，我们建立了在肝细胞中选择性地敲除HDAC1、HDAC2或两者的小鼠，以研究这些基因在肝部分切除或四氯化碳注射诱导的肝损伤后肝再生中的作用。HDAC1和/或HDAC2(HDAC1/2)蛋白缺失导致肝再生受损。HDAC1/2失活不会减少肝细胞5-溴-2-脱氧尿苷的摄取，也不会减少增殖细胞核抗原、细胞周期蛋白或细胞周期蛋白依赖性蛋白的表达。然而，与有丝分裂进程密切相关的有丝分裂标志物Ki67的表达水平显著降低，在HDAC1/2缺陷的肝脏中经常观察到缺乏Ki67表达的异常有丝分裂。在小鼠肝癌细胞系Hepa1-6中，HDAC1/2或Ki67的下调导致类似的有丝分裂缺陷。最后，HDAC1和HDAC2蛋白均与CCAAT/增强子结合蛋白介导的Ki67基因相关。结论：HDAC1和HDAC2在肝再生调节中起重要作用。HDAC1/2的缺失抑制了Ki67的表达，导致肝细胞有丝分裂障碍和肝再生受损。(《肝病》2013；58：2089-2098)
Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G(1) phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein . Conclusion: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. (Hepatology 2013; 58:2089-2098)