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.
This novel study, once completed, will help in clarifying how environmental toxin exposure poses a greater risk to the obese population for the development of steatohepatitis, chronic inflammatory conditions and autoimmune complications.
|Alhasson, Firas; Seth, Ratanesh Kumar; Sarkar, Sutapa et al. (2018) High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol 17:1-15|
|Chandrashekaran, Varun; Seth, Ratanesh K; Dattaroy, Diptadip et al. (2017) HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. Redox Biol 13:8-19|
|Seth, Ratanesh K; Das, Suvarthi; Dattaroy, Diptadip et al. (2017) TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med 102:260-273|
|Makris, Konstantinos C; Andrianou, Xanthi D; Charisiadis, Pantelis et al. (2016) Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus. Environ Int 92-93:486-93|
|Chandrashekaran, Varun; Das, Suvarthi; Seth, Ratanesh Kumar et al. (2016) Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 1862:32-45|
|Alhasson, Firas; Dattaroy, Diptadip; Das, Suvarthi et al. (2016) NKT cell modulates NAFLD potentiation of metabolic oxidative stress-induced mesangial cell activation and proximal tubular toxicity. Am J Physiol Renal Physiol 310:F85-F101|
|Dattaroy, Diptadip; Seth, Ratanesh Kumar; Das, Suvarthi et al. (2016) Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation. Am J Physiol Gastrointest Liver Physiol 310:G510-25|
|Burch, James B; Everson, Todd M; Seth, Ratanesh K et al. (2015) Trihalomethane exposure and biomonitoring for the liver injury indicator, alanine aminotransferase, in the United States population (NHANES 1999-2006). Sci Total Environ 521-522:226-34|
|Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar et al. (2015) M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice. J Pharmacol Exp Ther 352:77-89|
|Das, Suvarthi; Alhasson, Firas; Dattaroy, Diptadip et al. (2015) NADPH Oxidase-Derived Peroxynitrite Drives Inflammation in Mice and Human Nonalcoholic Steatohepatitis via TLR4-Lipid Raft Recruitment. Am J Pathol 185:1944-57|
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