PPARα protects against trans-fatty-acid-containing diet-induced steatohepatitis

Consumption of trans-fatty acids (TFA), unsaturated fatty acids (FA) containing trans double bonds, is a risk factor for metabolic syndrome and steatohepatitis. Peroxisome proliferator-activated receptor α (PPARα) is a master regulator of hepatic lipid homeostasis. To examine the contribution of PPARα to changes in liver phenotypes induced by TFA, two diets were used: a purified control diet and an isocaloric diet in which most of the soybean oil, a major source of FA in the diet, was replaced with TFA-rich shortening. The diets were fed to wild-type and Ppara-null mice for 2 months. Ppara-null mice fed a TFA-containing diet showed more severe hepatic steatosis and liver damage compared with similarly treated wild-type mice, as revealed by increased hepatic triglyceride (TG) contents and serum alanine aminotransferase activities. While the TFA-rich diet increased the hepatic expression of enzymes involved in de novo FA synthesis and decreased TG-hydrolyzing enzymes in both genotypes, the expression of FA-catabolizing enzymes was decreased in Ppara-null mice, resulting in more severe hepatosteatosis. Additionally, the expression levels of key contributors to inflammation, such as osteopontin, were increased, and nuclear factor-kappa B was activated in TFA-containing diet-fed Ppara-null mice. Enhanced inflammatory signaling in these mice was presumably mediated by toll-like receptor 2, with no accompanying inflammasome activation. Collectively, these results suggest a protective role for PPARα in the pathological changes in the liver following TFA consumption. PPARα might prevent TFA-containing diet-induced steatohepatitis.