High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis.

Obesity is linked to nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor-α (PPARα) regulates lipid metabolism. Cytochrome -450 2A5 (CYP2A5) is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1 dependent. High-fat diet (HFD)-induced obesity and steatosis are more severe in CYP2A5 knockout () mice than in wild-type mice although PPARα is elevated in mice. To examine why the upregulated PPARα failed to prevent the enhanced steatosis in mice, we abrogate the upregulated PPARα in mice by cross-breeding mice with PPARα knockout ) mice to create / mice. The / mice, mice, and mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in / mice than in mice and mice. The / mice and mice exhibited comparable and impaired lipid metabolism. Elevated serum alanine transaminase and liver interleukin-1β, liver inflammatory cell infiltration, and foci of hepatocellular ballooning were observed in / mice but not in mice and mice. In / mice, although redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 and its target antioxidant genes were upregulated as a compensation, thioredoxin was suppressed, and phosphorylation of JNK and formation of nitrotyrosine adduct were increased. Liver glutathione was decreased, and lipid peroxidation was increased. Interestingly, inflammation and fibrosis were all observed within the clusters of lipid droplets, and these lipid droplet clusters were all located inside the area with CYP2E1-positive staining. These results suggest that HFD-induced fibrosis in / mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.