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

Obesity is linked to non-alcoholic steatohepatitis. PPARα regulates lipid metabolism. 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 (cyp2a5-/-) mice than in wild-type mice although PPARα is elevated in cyp2a5-/- mice. To examine why the up-regulated PPARα failed to prevent the enhanced steatosis in cyp2a5-/- mice, we abrogate the up-regulated PPARα in cyp2a5-/- mice by cross-breeding cyp2a5-/- mice with PPARα knockout (pparα-/-) mice to create pparα-/-/cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice, pparα-/- mice, and cyp2a5-/- mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in pparα-/-/cyp2a5-/- mice than in pparα-/- mice and cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice and pparα-/-mice exhibited comparable and impaired lipid metabolism. Elevated serum ALT and liver IL-1β, liver inflammatory cell infiltration, foci of hepatocellular ballooning were observed in pparα-/-/cyp2a5-/- mice but not in pparα-/- mice and cyp2a5-/- mice. In pparα-/-/cyp2a5-/- mice, although redox sensitive transcription factor Nrf2 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 pparα-/-/cyp2a5-/- mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.

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