Nonalcoholic steatohepatitis and Cytochrome P450 Enzymes

非酒精性脂肪性肝炎和细胞色素 P450 酶

• 批准号: 7212797
• 负责人: NAGA P CHALASANI
• 金额: $ 25.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-21 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212797
• 关键词: Address; Adult; Age; Alcohol consumption; Alkane 1-monooxygenase; Animal Model; Animals; Anthropometry; Area; CYP2E1 gene; CYP4A11 gene; Characteristics; Child; Childhood; Chlorzoxazone; Chronic; Cytochrome P450; Data; Disulfiram; Enzymes; Fatty Acids; Fatty Liver; Fibrosis; Gender; Hepatic; Histologic; Histology; Human; Incidence; Individual; Inflammation; Injury; Insulin Resistance; Ketones; Lead; Lipid Peroxidation; Lipids; Liver; Liver Fibrosis; Liver diseases; Measures; Obesity; Oxidative Stress; Pathogenesis; Patients; Play; Population; Proteins; Research Personnel; Role; Serum; Source; Steatohepatitis; Testing; United States; adipokines; base; cytokine; enzyme activity; fibrogenesis; human study; in vivo; inhibitor/antagonist; insulin sensitizing drugs; mRNA Expression; nonalcoholic steatohepatitis; oxidation; programs; rosiglitazone; urinary

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.

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，以检验微粒体酶作为第二次打击在 NASH 发病机制中发挥作用的假设。我们将测量肥胖 NASH 中选定的微粒体酶的活性，并与单纯脂肪肝和正常肝脏组织学进行比较。我们还检查了选定的微粒体酶的活性与氧化应激、肝纤维化和纤维发生的标志物之间的关系，(2)我们将进行一项研究来检验这样的假设：胰岛素抵抗在 CYP2E1 活性增加的发病机制中发挥作用，并且通过服用罗格列酮来逆转胰岛素抵抗将降低 CYP2E1 活性。在这项研究中，我们将测量罗格列酮给药16周前后的肝脏CYP2E1活性以及血清和尿液脂质过氧化标志物的水平。（3）我们将通过测量肝脏CYP2E1活性和脂质水平来检验微粒体酶是NASH人类氧化应激和脂质过氧化的重要来源这一假设。 过氧化和施用基于选择性机制的 CYP2E1 抑制剂双（二乙基硫代氨基甲酰基）二硫化物，（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 的发病机制中发挥作用。我们将开展一项研究，以表征已知会在 NASH 儿童以及肥胖和瘦对照儿童中产生氧化应激的微粒体酶。此外，我们还研究了这种酶活性与胰岛素抵抗和脂质过氧化程度之间的关系。