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.
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Xiao
X
Hu
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan. Electronic address: naopi@shinshu-u.ac.jp.
Naoki
N
Tanaka
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Ran
R
Guo
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Yu
Y
Lu
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Takero
T
Nakajima
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Frank J
FJ
Gonzalez
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Toshifumi
T
Aoyama
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000628:therapy*; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D012307:Risk Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D044242:Trans Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects*; D014280:Triglycerides / Q000097:blood
D004041:Dietary Fats; D047493:PPAR alpha; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D044242:Trans Fatty Acids; D014280:Triglycerides; D000410:Alanine Transaminase
Inflammasome; Nuclear factor-kappa B; Osteopontin; PPARα; Toll-like receptor; trans-Fatty acid