Role of CYP2E1 in the Progression to NASH

描述（由申请人提供）：在非酒精性脂肪性肝病（NAFLD）中，启动肝细胞脂质积累并从良性脂肪变性进展为肝细胞损伤和慢性肝病的细胞信号是未知的。实验和人类NAFLD都与肝脏氧化应激以及促氧化细胞色素P450 （CYP）酶的过度表达有关。我们的一般假设是，这种疾病中的氧化应激改变了促进肝细胞损伤发展的细胞信号级联反应。过去资助期的研究已经确定了氧化应激对调节肝细胞损伤和死亡的丝裂原活化蛋白激酶（MARK）的影响。其他研究表明，CYP2E1过表达产生的氧化应激会改变肝脏代谢，包括胰岛素敏感性和脂质积累。基于这些研究和额外的初步数据，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展的关键机制。我们建议通过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，这些模型包含在四个特定目的中。首先，我们将验证Bim下调是cyp2e1过表达肝细胞抵抗氧化应激死亡的机制这一假设。其次，我们将验证cyp2e1过表达的肝细胞易受氧化还原依赖性磷酸酶抑制导致的JNK/AP- 1过度激活的假设。第三，我们将验证氧化诱导的JNK信号介导的胰岛素抵抗促进肝细胞脂肪变性的假设。第四，我们将验证在脂质积累背景下的氧化应激刺激JNK介导的内质网应激细胞死亡的假设。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展的基本细胞机制，以便设计新的策略来预防和治疗人类NAFLD。与公共卫生相关：NAFLD是一种非常普遍的肝脏疾病，目前尚无治疗方法。试图了解这种疾病中脂质积累和肝损伤的机制对于制定预防和治疗NAFLD的新策略非常重要。

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.