Free Radical Mechanism in Obesity Potentiation of Environmental Hepatotoxicity

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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.