Free Radical Mechanism in Obesity Potentiation of Environmental Hepatotoxicity

肥胖环境肝毒性增强中的自由基机制

• 批准号: 8708077
• 负责人: Saurabh Chatterjee
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708077
• 关键词: Autoimmune Process; CYP2E1 gene; Cell Death; Chemosensitization; Chronic; Development; Diet; Disinfection; Dose; Environment; Environmental Exposure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exposure to; Fatty Liver; Free Radical Formation; Free Radicals; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatotoxicity; In Vitro; Individual; Inflammation; Inflammatory; Instruction; Interferon Type II; Interferons; Isoenzymes; Knockout Mice; Lead; Leptin; Lipid Peroxidation; Macrophage Activation; Mus; NADPH Oxidase; Obese Mice; Obesity; Population; Proteins; Public Health; Research Project Grants; Risk; Risk Factors; Role; Steatohepatitis; System; Testing; Toxic Environmental Substances; Translations; Tumor Necrosis Factor-alpha; United States; adduct; dietary restriction; hepatotoxin; human TNF protein; in vivo; liver injury; neutralizing antibody; novel; oxidation; research study; response

Obesity associated Nonalcoriolic steatohepatitis (NASH), has become a growing public health concern with increased obesity population in the United States. Progression from steatosis (fatty liver) to steatohepatitis (fatty liver with inflammation) is thought to require a second hit. This second hit can be provided by environmental exposure to hepatotoxins that are reductively metaboiized to form reactive free radicals. Although direct exposure to high doses of environmental hepatotoxins is rare, low exposure from the environment is more com.mon. Low doses may be well tolerated by normal healthy individuals but can be potential risk factors for inflammatory liver injuries like steatohepatitis in obese persons. Thus the long term objective of this research project is to test the hypothesis that low hepatotoxin exposure from the environment can potentiate the risk of progression of steatohepatitis in obese mice. The hypothesis will be tested in three specific aims that include investigating the mechanism of free radical formation and post-translation oxidation adducts of proteins in obese mice in response to the disinfection byproduct (DBP) bromodichloromethane (BDCM). The specific aims will be achieved by using inhibitors of enzymes such as NADPH oxidase and the Cyp450 isozyme CYP2E1 and with knockout mice lacking each of these enzymes. All studies in obesity will be carried out in diet-induced obese (DIG) mice and compared to diet-restricted lean controls. In Aim 2, 1 shall examine how initial lipid peroxidation, interferon-gamma (IFN-y) and granulocyte macrophage colony stimulating factor (GMCSF) lead to activation of macrophages and contribute to the second wave of generation of free radical damage and TNF-alpha secretion following BDCM exposure. This aim will be achieved through experiments using both in vivo and in vitro systems, in aim 3, I shall investigate the role of the proinflammatory adipocytokine leptin in synergizing the effect of environmental hepatotoxins such as bromodichloromethane, a DBP, This aim will be achieved by investigating free radical-induced macrophage activation and cell death in Ieptin knockout mice and using neutralizing antibodies against Ieptin.

与肥胖相关的非氧化脂肪性肝炎（NASH）已成为美国肥胖人群增加的日益增长的公共卫生问题。从脂肪变性（脂肪肝）到脂肪性肝炎（炎症脂肪肝）的进展被认为需要第二次打击。第二次命中可以通过对环境暴露于还原为形成反应性自由基的肝毒素。尽管直接接触高剂量的环境肝毒素是很少见的，但环境的暴露率很低。正常健康个体可能会耐受低剂量的耐受性，但可能是炎症性肝损伤的潜在危险因素，例如肥胖者的脂肪性肝炎。因此，该研究项目的长期目标是检验以下假设：肥胖小鼠中肝炎的肝毒素暴露低可增强脂肪性肝炎的风险。该假设将在三个特定目的中进行检验，包括研究肥胖小鼠中蛋白质自由基形成的机制和响应消毒副产物（DBP）溴迪基氯甲烷（BDCM）的机制。通过使用诸如NADPH氧化酶和CYP450同工酶CYP2E1的酶的抑制剂以及缺少每种酶的敲除小鼠，将实现具体目标。肥胖症的所有研究都将在饮食引起的肥胖（挖掘）小鼠中进行，并将其与饮食受限的瘦对手进行比较。在AIM 2中，1应研究初始脂质过氧化，干扰素 - γ（IFN-Y）和粒细胞巨噬细胞群落刺激因子（GMCSF）导致巨噬细胞的激活，并有助于第二波自由基损伤和BDCM暴露后的TNF-Alpha分泌。在AIM 3中，我将通过使用体内和体外系统的实验来实现这一目标抗ieptin的抗体。