Abstract
Oxidative stress plays a key role in steatohepatitis induced by both xenobiotic agents and high fat diet (HFD). The present study aimed to evaluate hepatic oxidative stress and anti-oxidant systems response in rats exposed to HFD and/or non-toxic dose of dichlorodiphenyldichloroethylene (DDE), the first metabolite of dichlorodiphenyltrichloroethane. Groups of 8 rats were so treated for 4 weeks: 1- standard diet (N group); 2- standard diet plus DDE (10 mg/kg b.w.) (N+DDE group); 3- HFD (D group); 4- HFD plus DDE (D+DDE group). Oxidative stress was analyzed by determining malondialdehyde as lipid peroxidation product, while the anti-oxidant systems were evaluating by measuring the levels of the principal cytosolic and mitochondrial antioxidant proteins and enzymes, namely superoxide dismutase 1 and 2 (SOD1, SOD2), glutathione peroxidase 1 (GPx1) and uncoupling protein 2 (UCP2) involved in the control of hepatic reactive oxygens species (ROS) accumulation. The results showed malondialdehyde accumulation in livers of all groups, confirming the pro-oxidant effects of both HFD and DDE, but with a greater effect of DDE in absence of HFD. In addition, we found different levels of the analyzed anti-oxidant systems in the different groups. DDE mainly induced UCP2 and SOD2, while HFD mainly induced GPx1. Noteworthy, in the condition of simultaneous exposure to DDE and HFD, the anti-oxidant response was more similar to the one induced by HFD than to the response induced by DDE. Present findings confirmed that both HFD and xenobiotic exposure induced hepatic oxidative stress and showed that the anti-oxidant defense response was not the same in the diverse groups, suggesting that UCP2 induction could be an adaptive response to limit excessive ROS damage, mainly in condition of xenobiotic exposure.
Highlights
The liver is the main organ involved in xenobiotic detoxification as well as in dietary lipid metabolism, and hepatic steatosis is the most common pathologic liver responses to both high fat diet (HFD) and chemical exposures [1]
We first analysed whether the different treatments (HFD, DDE or HFD+DDE) differentially affected obesity development, and serum levels of metabolites related to lipid metabolism and hepatic injury (ALT and AST)
This work was carried out to study the cellular response, if any, to the toxic actions of the pesticide DDE in rat liver following a treatment of four weeks, in which DDE was administered alone or in combination with hyperlipidic diet to compare the effects of single exposure and simultaneous exposure to both environmental stimuli
Summary
The liver is the main organ involved in xenobiotic detoxification as well as in dietary lipid metabolism, and hepatic steatosis is the most common pathologic liver responses to both high fat diet (HFD) and chemical exposures [1]. We analyzed the effect of the simultaneous exposure to both HFD and DDE on the same markers of oxidative stress To this end, we determined the activation of the antioxidant enzymatic systems (SOD1-SOD2) and GPx1 response and we tested the hypothesis of mitochondrial uncoupling involvement to prevent ROS production in terms of UCP2 gene expression and protein synthesis in rat livers. Together with the activation of the antioxidant enzymatic systems, a difference in UCP2 modulation according to the treatments used, with the highest induction of UCP2 in the hepatocytes of DDE-treated animals From these data we assumed that UCP2 plays a protective role to limit cell damage and liver injury mitigating mitochondrial ROS production with an increasing functional impact at increasing levels of oxidative stress
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