Role of CYP2E1 in the Progression to NASH

描述（由申请人提供）：非酒精性脂肪肝（肝 脂肪变性）可通过未知机制进展为非酒精性脂肪性肝炎 NASH是一种以肝细胞损伤和死亡、炎症和 纤维化人NASH和NASH的动物模型都与以下相关： 促氧化酶细胞色素P450 2 E1（CYP 2 E1）的表达增加。我们 假设持续的CYP 2 EI表达促进了从 通过氧化剂介导的细胞死亡信号转导改变的脂肪变性至NASH 使肝细胞对NASH相关损伤和死亡敏感的途径 辅因子如肿瘤坏死因子-α（TNF-α）和多不饱和脂肪酸 acids.为了验证这一假设，我们开发了一种新的， 具有差异CYP 2 E1表达的肝细胞系。初步研究 已经证明，CYP 2 E1表达增加使肝细胞对 与丝裂原活化蛋白改变相关的死亡刺激 激酶信号传导、转录因子激活和细胞谷胱甘肽 内容这项建议的目标是确定分子机制， CYP 2 E1表达增加促进肝细胞死亡，并有助于 从脂肪变性到NASH的进展。这项建议的具体目标是 目的：（1）确定CYP 2 E1表达增加致敏的机制 肝细胞对TNF-α和多不饱和脂肪酸的损伤和细胞死亡的影响 acids. (2)确定AP-1转录激活为最终下游 CYP 2 E1表达肝细胞中的细胞死亡效应子。(3)定义细胞 CYP 2 E 1表达诱导的变化，促进细胞坏死死亡 而不是凋亡。(4)检测脂多糖和TNF-α的能力 以在体内NASH模型中触发向脂肪性肝炎的进展。的 这些调查的最终目的是更好地了解 导致脂肪变性进展为脂肪性肝炎的机制， 开发新的治疗方法来预防肝细胞损伤， 纳什

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver (hepatic steatosis) can progress by unknown mechanisms to nonalcoholic steatohepatitis (NASH) that is characterized by hepatocyte injury and death, inflammation and fibrosis. Both human NASH and animal models of NASH are associated with increased expression of the pro-oxidant enzyme cytochrome P450 2E1 (CYP2E1). We hypothesize that sustained CYP2EI expression promotes the progression from steatosis to NASH through oxidant-mediated alterations in cell death signaling pathways that sensitize hepatocytes to injury and death from NASH-related cofactors such as tumor necrosis factor-a (TNF-ct) and polyunsaturated fatty acids. To test this hypothesis we have developed novel, nontransformed hepatocyte cell lines with differential CYP2E1 expression. Preliminary studies have demonstrated that increased CYP2E1 expression sensitizes hepatocytes to death stimuli in association with alterations in mitogen-activated protein kinase signaling, transcription factor activation, and cellular glutathione content. The goal of this proposal is to determine the molecular mechanisms by which increased CYP2E1 expression promotes hepatocyte death, and contributes to the progression from steatosis to NASH. The specific aims of this proposal are to: (1) Determine the mechanism by which increased CYP2E1 expression sensitizes hepatocytes to injury and cell death from TNF-a and polyunsaturated fatty acids. (2) Identify AP-1 transcriptional activation as the ultimate downstream effector of cell death in CYP2E1-expressing hepatocytes. (3) Define cellular changes induced by CYP2E 1 expression that promote cell death from necrosis rather than apoptosis. (4) Examine the ability of lipopolysaccharide and TNF-a to trigger the progression to steatohepatitis in an in vivo NASH model. The ultimate objective of these investigations is to better understand the mechanisms leading to the progression of steatosis to steatohepatitis, in order to develop new therapies to prevent the hepatocyte injury that underlies human NASH.