PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats

Peroxisome proliferator-activated receptor (PPAR) alpha/gamma may control lipid metabolism and inflammatory response by regulating the downstream target genes, and play a crucial role in the process of non-alcoholic steatohepatitis (NASH) formation, but the difference and interaction between PPAR alpha and PPAR gamma are poorly understood. The rat model with NASH was established by orally feeding high-fat and high-sucrose emulsion for 6 weeks. The results shown that after the model rats were simultaneously treated with PPAR alpha/gamma agonists, the total cholesterol (TC), triglyceride (TG) and inflammatory cytokine levels in serum and hepatic tissue, the hepatic steatosis and inflammatory cellular infiltration were decreased, and were consistent with the results of hepatic lipogenic gene and nuclear factor (NF)-kappa B protein expressions. Conversely, these indexes were increased by PPAR alpha/gamma antagonist treatment. Compared with the model group, the serum free fatty acid (FFA) level was increased in the PPAR alpha agonist-treated group, decreased in the PPAR gamma agonist-treated group, and unchanged in the PPAR alpha/gamma agonists-treated group. The hepatic FFA level was low in the PPAR alpha/gamma agonists-treated groups, but no significant variation in the PPAR alpha/gamma antagonists-treated groups. The increments of hepatic reduced glutathione (GSH) and superoxide dismutase (SOD) contents in the PPAR alpha/gamma agonists-treated groups were accompanied by decreased hepatic malondialdehyde (MDA) content. These findings demonstrated that PPAR alpha/gamma activation might decrease the hepatic lipid accumulation, oxidative stress and inflammatory cytokine production, and PPAR gamma could counterbalance the adverse effect of PPAR alpha on circulating FFA. It was concluded that the integrative application of PPAR alpha and PPAR gamma agonists might exert a synergic inhibitory effect on NASH formation through the modulation of PPAR alpha/gamma-mediated lipogenic and inflammatory gene expressions. (C) 2015 Elsevier Ltd. All rights reserved.