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

基本信息

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
项目类别：
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

项目摘要

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.

随着美国肥胖人口的增加，与肥胖相关的非酒精性脂肪性肝炎（NASH）已成为日益严重的公共卫生问题。从脂肪变性（脂肪肝）进展到脂肪性肝炎（脂肪肝伴炎症）被认为需要第二次打击。第二次打击可以通过环境暴露于肝毒素来提供，这些肝毒素被还原代谢形成反应性自由基。尽管直接暴露于高剂量环境肝毒素的情况很少见，但低剂量暴露于环境的情况更为常见。正常健康个体可以很好地耐受低剂量，但可能是肥胖者脂肪性肝炎等炎性肝损伤的潜在危险因素。因此，该研究项目的长期目标是检验以下假设：环境中低肝毒素暴露会增加肥胖小鼠脂肪性肝炎进展的风险。该假设将在三个具体目标上进行测试，包括研究肥胖小鼠中自由基形成和蛋白质翻译后氧化加合物对消毒副产物 (DBP) 溴二氯甲烷 (BDCM) 的反应的机制。具体目标将通过使用 NADPH 氧化酶和 Cyp450 同工酶 CYP2E1 等酶抑制剂以及缺乏这些酶中每种酶的基因敲除小鼠来实现。所有肥胖研究都将在饮食诱导肥胖 (DIG) 小鼠中进行，并与饮食限制的瘦对照小鼠进行比较。在目标 2 中，1 应检查初始脂质过氧化、干扰素 γ (IFN-y) 和粒细胞巨噬细胞集落刺激因子 (GMCSF) 如何导致巨噬细胞活化并促成第二波自由基损伤和 TNF-α 的产生BDCM 暴露后的分泌。这一目标将通过使用体内和体外系统的实验来实现，在目标3中，我将研究促炎脂肪细胞因子瘦素在协同环境肝毒素（例如溴二氯甲烷，一种DBP）的作用中的作用，该目标将通过研究瘦素敲除小鼠中自由基诱导的巨噬细胞活化和细胞死亡，并使用针对瘦素的中和抗体。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

P2X7 receptor-NADPH oxidase axis mediates protein radical formation and Kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice.

P2X7 受体-NADPH 氧化酶轴介导肥胖小鼠四氯化碳介导的脂肪性肝炎中蛋白质自由基的形成和库普弗细胞活化。

DOI：
10.1016/j.freeradbiomed.2012.02.010
发表时间：
2012-05-01
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Chatterjee, Saurabh;Rana, Ritu;Corbett, Jean;Kadiiska, Maria B.;Goldstein, Joyce;Mason, Ronald P.
通讯作者：
Mason, Ronald P.

The janus of oxidative stress signaling in different pathophysiological conditions.

不同病理生理条件下氧化应激信号传导的两面性。

DOI：
发表时间：
2013
期刊：
影响因子：
0
作者：
Miriyala, Sumitra;Panchatcharam, Manikandan;Landar, Aimee;Ramanujam, Meera;Chatterjee, Saurabh;Muthuswamy, Anantharaman
通讯作者：
Muthuswamy, Anantharaman

Detection and imaging of the free radical DNA in cells--site-specific radical formation induced by Fenton chemistry and its repair in cellular DNA as seen by electron spin resonance, immuno-spin trapping and confocal microscopy.

细胞中自由基 DNA 的检测和成像——芬顿化学诱导的位点特异性自由基形成及其通过电子自旋共振、免疫自旋捕获和共聚焦显微镜观察到的细胞 DNA 修复。

DOI：
发表时间：
2012-07
期刊：
影响因子：
14.9
作者：
Bhattacharjee, Suchandra;Chatterjee, Saurabh;Jiang, Jinjie;Sinha, Birandra Kumar;Mason, Ronald P
通讯作者：
Mason, Ronald P

P2X7 receptor as a key player in oxidative stress-driven cell fate in nonalcoholic steatohepatitis.

P2X7 受体在非酒精性脂肪性肝炎氧化应激驱动的细胞命运中发挥关键作用。

DOI：
发表时间：
2015
期刊：
影响因子：
0
作者：
Chatterjee, Saurabh;Das, Suvarthi
通讯作者：
Das, Suvarthi

Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus.

溴化三卤甲烷暴露、肝损伤和 II 型糖尿病之间的关联。

DOI：
10.1016/j.envint.2016.04.012
发表时间：
2016-07-01
期刊：
Environment international
影响因子：
11.8
作者：
K. Makris;X. Andrianou;P. Charisiadis;J. Burch;R. Seth;Androniki Ioannou;M. Picolos;C. Christophi;S. Chatterjee
通讯作者：
S. Chatterjee