Nonalcoholic steatohepatitis and Cytochrome P450 Enzymes

描述（由申请人提供）：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，我们建议开展以下人体研究。(1)我们将开展一项研究来验证微粒体酶作为二次打击在NASH发病机制中发挥作用的假设。我们将测量选定的微粒体酶在肥胖NASH患者中的活性，并将其与单独脂肪肝和正常肝脏组织进行比较。我们还研究了所选微粒体酶的活性与氧化应激、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，以验证胰岛素抵抗在CYP2E1活性升高的发病机制中起作用的假设，而罗格列酮的逆转会降低CYP2E1活性。在这项研究中，我们将测量肝脏CYP2E1活性和血清和尿液脂质过氧化标志物在罗格列酮给药16周前后的水平。(3)我们将测试微粒体酶是NASH患者氧化应激和脂质过氧化的重要来源的假设，方法是在使用选择性机制的CYP2E1抑制剂双（二乙基硫代氨基甲酰基）二硫化物之前测量肝脏CYP2E1活性和脂质过氧化水平。(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。目前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，以表征一种微粒体酶，这种酶已知会在NASH儿童和肥胖和瘦肉对照中产生氧化应激。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.