Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically
Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically
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DOI：
10.3748/wjg.15.705
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发表时间：
2009-02-14
影响因子：
4.3
通讯作者：
Bardag-Gorce, Fawzia
中科院分区：
文献类型：
--
作者：
Oliva, Joan;Dedes, Jennifer;Bardag-Gorce, Fawzia
目的：方法：使用Tsukamoto-French模型给大鼠喂食乙醇1个月，并与通过腹腔注射给予蛋白酶体抑制剂PS-341（Bortezaline，Velcade（TM））的大鼠进行比较。微阵列分析和真实的时间PCR和蛋白酶体活性测定和Western印迹分析进行了分离nucleus.RESULTS：慢性乙醇喂养引起了显着抑制的泛素蛋白酶体途径在细胞核中，从而导致转录因子，组蛋白修饰酶的营业额的变化，因此，影响表观遗传机制。慢性乙醇喂养与组蛋白乙酰化的增加有关，并且假设蛋白酶体蛋白水解活性通过控制组蛋白修饰酶的稳定性来调节组蛋白修饰，并且因此调节染色质结构，允许RNA聚合酶容易地进入染色质，并且因此适当的基因表达。PS-341的蛋白酶体抑制增加组蛋白乙酰化类似于慢性乙醇喂养。此外，蛋白酶体抑制引起肝脏再甲基化反应的显著变化，因为负责S-腺苷甲硫氨酸再生的酶显著减少，特别是甜菜碱-高半胱氨酸甲基转移酶显著减少。这表明，低甲基化与蛋白酶体抑制，组蛋白methylation.CONCLUSION减少所示：蛋白酶体抑制在调节表观遗传机制的作用，其链接到酒精性肝病肝损伤，因此是一个很有前途的方法来研究由于慢性乙醇消耗肝损伤。(C)2009年，WIG出版社和百世登。All rights reserved.
AIM: To examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.METHODS: Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 (Bortezomib, Velcade (TM)) by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei.RESULTS: Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation.CONCLUSION: The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption. (C) 2009 The WIG Press and Baishideng. All rights reserved.