Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells.
Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells.
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乙醇对小鼠肝星状细胞芳基烃受体活性和表达的调节。
DOI：
10.1111/j.1530-0277.2012.01787.x
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Guo,ZhongMao
中科院分区：
文献类型：
--
作者：
Zhang,HongFeng;Lin,XingHua;Yang,Hong;Zhou,LiChun;Guo,YangLin;Barnett,JoeyV;Guo,ZhongMao
背景在酒精性肝损伤过程中，肝星状细胞转化为增殖性、纤维化性和收缩性肌成纤维细胞。芳烃受体（AhR）是一种转录因子，控制参与代谢的外源性物质，炎症，细胞增殖，和death.MethodsImmortal小鼠肝星状细胞（MHSC）的基因的表达从转基因小鼠表达的热不稳定性SV40肿瘤抗原分离。定量真实的实时逆转录聚合酶链反应分析，蛋白质印迹分析，启动子活性测定，染色质免疫沉淀分析进行研究乙醇（EtOH）对AhR表达和转录activity.ResultsTreatment的MHSC与50至200 mM EtOH 6小时诱导AhR核转位，增强细胞色素P450（CYP1A1）的启动子活性，增加与CYP1A1和1B1启动子结合的AhR量，并以剂量依赖性方式上调这些AhR靶基因的mRNA表达。相反，乙醇暴露下调AhR mRNA和蛋白质表达。类似地，10 nM的苯并（a）芘（BaP）降低AhR并增加CYP1A1和1B1 mRNA。用50 mM EtOH预处理MHSC 7天，降低了MHSC表达由200 mM EtOH激发或10 nM BaP诱导的CYP1A1和1B1的能力。然而，EtOH对溶质载体家族16成员6（SLC 16a6）的上调作用不受EtOH预处理的影响。类似于乙醇，二甲基亚砜（DMSO）在50至100 mM的浓度下调AhR和上调CYP1A1 mRNA的表达在剂量依赖martens.ConclusionsThese数据，第一次，证明乙醇激活MHSC AhR和下调其表达。慢性EtOH预处理降低了AhR的可用性，特别是降低了CYP基因的诱导性。对AhR的影响似乎不是EtOH特异性反应，因为单独的DMSO（以及可能的其他有机溶剂）也能够激活AhR。
BackgroundDuring the course of alcohol‐induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death.MethodsImmortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real‐time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity.ResultsTreatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up‐regulated the mRNA expression of these AhR target genes in a dose‐dependent manner. In contrast, EtOH exposure down‐regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up‐regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down‐regulated AhR and up‐regulated CYP1A1 mRNA expression in a dose‐dependent manner.ConclusionsThese data, for the first time, demonstrate that EtOH activates MHSC AhR and down‐regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH‐specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR.
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