Nonalcoholic steatohepatitis and Cytochrome P450 Enzymes

描述(申请人提供)：非酒精性脂肪性肝炎是一种常见的慢性肝病，但其发病机制尚不清楚。最近的动物研究表明，微粒体酶可能在非酒精性脂肪性肝炎(NASH)的发病机制中发挥作用。为了进一步了解微粒体酶在NASH发病机制中的作用，我们建议进行以下人体研究。(1)我们将进行一项研究，以检验微粒体酶在NASH发病机制中发挥作用的假设，作为第二次打击。我们将与单纯脂肪肝和正常肝组织学相比较，测量患有NASH的肥胖者所选择的微粒体酶的活性。我们还研究了部分微粒体酶活性与氧化应激、肝纤维化和纤维化标志物之间的关系。(2)我们将进行一项研究，以检验胰岛素抵抗在CYP2E1活性升高的发病机制中所起的作用，并通过罗格列酮的治疗逆转这一假说。在本研究中，我们将在罗格列酮治疗16周前和16周后检测肝脏CYP2E1活性以及血清和尿液中脂质过氧化标志物的水平。(3)我们将通过检测服用基于选择性机制的CYP2E1抑制剂二(二乙基硫代氨基甲酰)二硫化物前和给予选择性机制基础上的双(二乙基硫代氨基甲酰)二硫化物来验证微粒体酶是人类NASH氧化应激和脂质过氧化的重要来源的假说。(4)研究表明微粒体酶可能在成人NASH的发病机制中发挥作用，但尚不清楚它们是否在儿童NASH的发病机制中起作用。我们将进行一项研究，以确定一种已知的在NASH、肥胖和瘦控制儿童中产生氧化应激的微粒体酶的特征。此外，我们还研究了这种酶的活性与胰岛素抵抗和脂质过氧化程度之间的关系。

DESCRIPTION (provided by applicant): Nonalcoholic steatohepatitis is a common chronic liver disease but its pathogenesis is not well understood. Recent animal studies have suggested that microsomal enzymes may play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). In order to further understand the role of microsomal enzymes in the pathogenesis of NASH, we propose to conduct the following human studies. (1) We will conduct a study to test the hypothesis that microsomal enzymes play a role in the pathogenesis of NASH as a second hit. We will measure the activity of selected microsomal enzymes in obese with NASH as compared to fatty liver alone and normal liver histology. We also examine the relationship between the activity of selected microsomal enzymes and markers of oxidative stress, hepatic fibrosis and fibrogenesis, (2) We will conduct a study to test the hypothesis that insulin resistance plays a role in the pathogenesis of increased CYP2E1 activity, and its reversal by the administration of rosiglitazone will lower the CYP2E1 activity. In this study, we will measure the hepatic CYP2E1 activity and the levels of serum and urinary markers of lipid peroxidation before and after the administration of rosiglitazone for 16 wks., (3) We will test the hypothesis that microsomal enzymes are an important source of oxidative stress and lipid peroxidation in humans with NASH by measuring the levels of hepatic CYP2E1 activity and lipid peroxidation before and administering a selective mechanism-based CYP2E1 inhibitor, bis (diethylthiocarbamoyl) disulfide, (4) Studies have suggested that microsomal enzymes may play a role in the pathogenesis of NASH in adults, however, it is unknown if they play any role in the pathogenesis of NASH in children. We will conduct a study to characterize a microsomal enzyme known to generate oxidative stress in children with NASH and obese and lean controls. Additionally, we examine the relationship between this enzyme activity and the degree of insulin resistance and lipid peroxidation.