PPARγ Agonists Alleviate the High Fat-induced Oxidative Stress and Inflammatory Response in vitro and in vivo Through Nrf2-mediated Antioxidant Pathway / 胃肠病学

ABSTRACT

Background: Oxidative stress is important for the development and progress of non-alcoholic fatty liver disease. Recent studies have demonstrated the anti-inflammatory and antioxidant activities of peroxisome proliferator-activated receptor γ (PPARγ) agonists. Aims: To investigate the protective effect of PPARγ agonists (rosiglitazone and GW1929) on high fat-induced hepatocyte oxidative stress injury in vitro and in vivo and the underlying mechanism. Methods: C57BL/6J mice were fed with high-fat diet and administered intragastrically with rosiglitazone 30 mg/kg per day for 4 weeks. The primary mouse hepatocytes were isolated and incubated with mixed free fatty acids (FFA) after GW1929 pretreatment. HE staining and oil red staining were used to evaluate the histopathological changes and lipid deposition in the liver. Serum contents of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were measured. Reactive oxygen species (ROS) in hepatocytes was detected by DCFH-DA fluorescence probe. Real-time PCR and Western blotting were used to detect the expressions of genes related to oxidative stress and inflammation. Results: High-fat diet induced significant hepatic steatosis and up-regulated gene expressions of inflammatory cytokines. Serum MDA content was significantly increased, and SOD activity and GSH content were significantly decreased. Rosiglitazone intervention could reduce the high fat-induced hepatic steatosis, inflammation and improve the serum indicators of oxidative stress. Primary hepatocytes incubated with FFA produced a large amount of ROS, whereas GW1929 pretreatment could diminish the FFA-induced ROS production, inflammation and increase the antioxidant factors, nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene heme oxygenase-1 (HO-1) expression. Conclusions: High-fat environment can induce steatosis, oxidative stress and inflammation in hepatocytes in vitro and in vivo. PPARγ agonists may alleviate the high fat-induced oxidative stress injury and inflammatory response through inhibiting ROS production and activating Nrf2/HO-1 antioxidant pathway.