Role of CYP2E1 in the Progression to NASH

描述(申请人提供)：在非酒精性脂肪性肝病(NAFLD)中，启动肝细胞脂肪堆积和进展的细胞信号尚不清楚，从良性脂肪变性到肝细胞损伤和慢性肝病。实验性和人类NAFLD都与肝脏氧化应激以及细胞色素P450(CYP)酶的过度表达有关。我们的一般假设是，这种疾病的氧化应激改变了细胞信号级联反应，从而促进了肝细胞损伤的发展。在过去的资金支持期间，研究已经明确了氧化应激对调节肝细胞损伤和死亡的丝裂原激活蛋白激酶(MARK)的影响。其他研究表明，由CYP2E1过度表达产生的氧化应激改变了肝脏代谢，包括胰岛素敏感性和脂质积累。基于这些研究和更多的初步数据，我们的中心假设是，慢性氧化应激导致的MAPK信号过度激活是肝脏脂肪变性和损伤发生的关键机制。我们建议通过对肝细胞和体内脂肪变性和氧化应激模型的研究来验证这一假设，这些研究包含四个特定的目标。首先，我们将检验一种假设，即Bim下调是高表达的肝细胞抵抗氧化应激死亡的机制。其次，我们将验证一种假设，即由于氧化还原依赖的磷酸酶抑制，过度表达的肝细胞容易受到促凋亡的JNK/AP-1过度激活的影响。第三，我们将检验氧化诱导的JNK信号介导的胰岛素抵抗促进肝细胞脂肪变性的假说。第四，我们将验证假设，氧化应激在脂质积累的背景下刺激JNK介导的内质网应激导致的细胞死亡。这些研究的最终目的是为了更好地了解导致脂肪变性和脂肪性肝炎发生的基本细胞机制，以便设计新的策略来预防和治疗人类NAFLD。与公众健康相关：非酒精性脂肪肝是一种非常普遍的肝病，目前还没有已知的治疗方法。试图了解这种疾病的脂质堆积和肝脏损伤的机制，对于开发新的防治策略具有重要意义。

DESCRIPTION (provided by applicant): In nonalcoholic fatty liver disease (NAFLD) the cellular signals that initiate hepatocyte lipid accumulation and progression from benign steatosis to hepatocyte injury and chronic liver disease are unknown. Both experimental and human NAFLD are associated with hepatic oxidative stress along with overexpression of prooxidant cytochrome P450 (CYP) enzymes. Our general hypothesis has been that oxidative stress in this disease alters cell signaling cascades that promote the development of hepatocyte injury. Investigations over the past funding period have defined effects of oxidative stress on mitogen-activated protein kinases (MARK) that regulate hepatocyte injury and death. Other studies have demonstrated that oxidative stress generated by CYP2E1 overexpression alters hepatic metabolism including insulin sensitivity and lipid accumulation. Based on these studies and additional preliminary data, our central hypothesis is that overactivation of MAPK signaling by chronic oxidative stress is a critical mechanism in the development of both hepatic steatosis and injury. We propose to test this hypothesis with studies in hepatocyte and in vivo models of steatosis and oxidative stress that are contained in four specific aims. First, we will test the hypothesis that Bim down regulation is the mechanism by which CYP2E1-overexpressing hepatocytes resist death from oxidant stress. Second, we will test the hypothesis that CYP2E1-overexpressing hepatocytes are susceptible to proapoptotic JNK/AP- 1 overactivation because of redox-dependent phosphatase inhibition. Third, we will test the hypothesis that insulin resistance mediated by oxidant-induced JNK signaling promotes hepatocyte steatosis. Fourth, we will test the hypothesis that oxidative stress in the setting of lipid accumulation stimulates JNK mediated cell death from endoplasmic reticulum stress. The ultimate goal of these investigations is to better understand the basic cellular mechanisms that lead to the development of steatosis and steatohepatitis in order to design new strategies to prevent and treat human NAFLD. Relevance to public health: NAFLD is a very prevalent liver disease which has no known treatment. Attempts to understand the mechanisms of lipid accumulation and liver injury in this disease are important to the development of new strategies for the prevention and treatment of NAFLD.