High fat diet and environmental pollutants exposure: mitochondrial uncoupling as protective mechanism toward hepatic injury in rats.

Liver is the main organ involved in dietary lipid handling and xenobiotic detoxification. Mitochondrial dysfunction and oxidative stress play a key role in hepatic injury. This study aimed to investigate oxidative stress, mitochondrial dysfunction and uncoupling in response to exposure to high fat diet (HFD) and/or non-toxic dose of the environmental pollutant dichloro diphenyldichloroethylene (DDE, the first metabolite of DDT). Groups of rats were so treated: 1- standard diet (N group); 2- standard diet plus oral administration of DDE (10 mg/kg b.w.) (N+DDE group); 3- HFD (D group); 4- HFD plus DDE (D+DDE group). Oxidative stress, mitochondrial fatty acid oxidation and uncoupling protein 2 (UCP2) expression/content were analyzed. D rats showed increased hepatic lipid accumulation and fatty acid oxidation associated with increased oxidative stress and UCP2 content. Enhanced fatty acid oxidation leads to increased ROS production which can be controlled by mitochondrial uncoupling that, by increasing proton leak back to the matrix, contributes to regulate the excess superoxide production by the electron transport chain. DDE treated- groups also showed increases in hepatic injury, fatty acid oxidation and oxidative stress, but with a higher increase in hepatocytes UCP2 content vs. D group, mainly when associated with a normal diet. Noteworthy, UCP2 in liver of control rats was expressed only in immunocompetent cells, whereas the oxidative stress, produced by HFD and/or DDE, induced mRNA synthesis and protein translation in hepatocytes too. Present findings confirmed that both HFD and xenobiotic exposure induced hepatic oxidative stress and showed that the UCP2 induction could be an adaptive response to limit excessive ROS damage, mainly in condition of xenobiotic exposure.