The Protective Role of Per2 Against Carbon Tetrachloride-induced Hepatotoxicity
The Protective Role of Per2 Against Carbon Tetrachloride-induced Hepatotoxicity
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Per2 对四氯化碳引起的肝毒性的保护作用
DOI：
10.2353/ajpath.2009.080430
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发表时间：
2009-01-01
影响因子：
6
通讯作者：
Zhang, Jianfa
中科院分区：
文献类型：
--
作者：
Chen, Peng;Li, Chunying;Zhang, Jianfa
周期2 （Per2）是核心时钟振荡器的关键组成部分，参与调节许多不同的生物过程和途径。在这里，我们报道Per2通过调节解偶联蛋白-2 （Ucp2）基因表达在小鼠四氯化碳（CCl4）诱导的肝毒性中起保护作用。在野生型和Per2-null小鼠中监测急性注射CCl4后的肝损伤。在CCl4治疗后的12小时时间点，Per2-null小鼠的肝脏组织中观察到更多的空泡化，而宽型小鼠的肝脏组织主要发生脂肪组织变性。在CCl4治疗24小时后，per2缺失小鼠的血清丙氨酸和天冬氨酸转氨酶活性比宽型小鼠升高，这与per2缺失小鼠肝脏小叶中心坏死面积明显增大的观察结果一致。Per2基因的缺失增强了肝脏中Ucp2基因的表达水平。结果，肝脏细胞内ATP水平显著下降，导致有毒CCl4衍生物的产生增加。Per2表达缺失导致Clock表达显著升高，并通过涉及Clock控制的PPAR-a信号转导途径的机制影响Ucp2。我们的研究表明，Per2基因通过调节肝脏Ucp2基因的表达水平来保护肝细胞免受化学毒物的侵害。[J] .中华病理学杂志，2009,(4):63-70；10.2353 / ajpath.2009.080430)
Period 2 (Per2) is a key component of the core clock oscillator and is involved in regulating a number of different biological processes and pathways. Here we report that Per2 plays a protective role in carbon tetrachloride (CCl4)-induced hepatotoxicity via the modulation of uncoupling protein-2 (Ucp2) gene expression in mice. Hepatic injury after acute CCl4 injection was monitored in both wild-type and Per2-null mice. At the 12-hour time point after CCl4 treatment, many more vacuolations were observed in the liver tissues of Per2-null mice whereas fatty tissue degeneration primarily occurred in the liver tissues of wide-type mice. Serum alanine and aspartate aminotransferase activities were elevated in Per2-null mice compared with wide-type mice at 24 hours after CCl4 treatment, which was in agreement with the observation of significantly larger areas of centrilobular necrosis in the livers of Per2-null mice. A deficit of the Per2 gene enhanced Ucp2 gene expression levels in the liver. As a consequence, intracellular levels of ATP markedly decreased in the liver, allowing increased production Of toxic CCl4 derivatives. The absence of Per2 expression caused a dramatic elevation of Clock expression and influenced Ucp2 through a mechanism that involved a Clock-controlled PPAR-a signal transduction pathway. Our studies suggest that the Per2 gene functions in hepatocyte protection from chemical toxicants via the regulation of hepatic Ucp2 gene expression levels. (Am J Pathol 2009, 174:63-70; DOI. 10.2353/ajpath.2009.080430)