Liver fibrosis and ethanol: role of the transcription factor, Egr-1

酒精性肝纤维化是一种严重的肝病。尽管在这方面取得了长足的进步 了解纤维化形成的机制以及如何解决它，这些发现 还没有带来更好的治疗策略。EGR-1是一种转录因子，调节一系列广泛的 参与炎症和伤口愈合反应的基因。EGR-1是乙醇诱导的一种重要调节剂 小鼠脂肪肝和急性肝炎。由于Egr-1具有调节基因的能力 调节纤维化，我们假设Egr-1是毒素介导的肝纤维化的重要贡献者 肝脏损伤。事实上，在该奖项的K99部分期间完成的最近发表的作品揭示了 在缺乏Egr-1的小鼠中，四氯化碳(CCI4)诱导的肝纤维化得到加强。增强型纤维化 与减少肝脏保护、更严重的肝损伤和肝细胞进入延迟有关 急性CCI4暴露后EGR-1-/-小鼠进入和通过细胞周期。激活椭圆形 EGR-1-/-小鼠在慢性CCW暴露后的细胞反应与这些发现一致。总的来说，我们的 研究表明，Egr-1作为一个关键的调节器，肝脏对肝毒素的反应和 纤维化过程。 酒精喂养小鼠产生有限的纤维化，需要使用肝毒性药物，如CCi4 探讨肝纤维化的发生机制。为了更好地了解酒精暴露对纤维化形成的影响，我们 开发了一种新的模型，利用这种模型，我们可以使用低水平的乙醇(2%v/v乙醇为5 天至2周)，并结合急性或慢性《特定常规武器公约》暴露。重要的是，CYP2E1，这种酶 在慢性乙醇暴露后肝脏中被激活和诱导，两者之间没有区别 对照组和乙醇喂养的小鼠暴露在这个剂量的乙醇中。使用该模型，以及原发肝脏 星状细胞培养，我们将继续剖析Egr-1促进 通过完成最初描述的三个具体目标来实现纤维化。

Ethanol-induced hepatic fibrosis is a severe form of liver disease. Although great strides have been made in understanding the mechanisms by which fibrosis is established and how it resolves, these discoveries have not yet lead to improved therapeutic strategies. Egr-1 is a transcription factor that regulates a broad array of genes involved in inflammation and the wound-healing response. Egr-1 is a critical modulator of ethanolinduced fatty liver and acute hepatic inflammation in mice. Due to the ability of Egr-1 to regulate genes that modulate fibrosis, we hypothesize that Egr-1 is an important contributor to liver fibrosis after toxin-mediated liver injury. Indeed, recently published work completed during the K99 portion of this award revealed that carbon tetrachloride (CCI4)-induced liver fibrosis is enhanced in mice deficient in Egr-1. Enhanced fibrosis was associated with reduced hepatoprotection, more severe liver injury and a delay in hepatocyte entrance into and progression through the cell cycle in egr-1-/- mice after acute CCI4 exposure. Activation of the oval cell response in egr-1-/- mice after chronic CCW exposure is consistent with these findings. Collectively, our studies suggest novel roles for Egr-1 as a critical modulator the liver's response to hepatotoxins and the fibrogenic process. Ethanol feeding to mice produces limited fibrosis necessitating the use of hepatotoxicants such as CCi4 to explore mechanisms of fibrosis. To better understand the effects of ethanol exposure on fibrogenesis, we developed a new model with which we can 'accelerate' fibrosis using low-level ethanol (2% v/v ethanol for 5 days to 2 weeks) in combination with acute or chronic CCW exposure. Importantly, CYP2E1, the enzyme required for CCW bioactivation and induced in liver after chronic ethanol exposure, is not different between control and ethanol-fed mice exposed to this dose of ethanol. Using this model, as well as primary hepatic stellate cell cultures, we will continue to dissect the molecular mechanisms by which Egr-1 contributes to fibrosis through completion of the three Specific Aims as originally described.