| First Author | Chen X | Year | 2020 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 319 |
| Issue | 5 | Pages | G626-G635 |
| PubMed ID | 32877213 | Mgi Jnum | J:307085 |
| Mgi Id | MGI:6710870 | Doi | 10.1152/ajpgi.00213.2020 |
| Citation | Chen X, et al. (2020) High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARalpha: a new model for steatohepatitis-associated fibrosis. Am J Physiol Gastrointest Liver Physiol 319(5):G626-G635 |
| abstractText | Obesity is linked to nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates lipid metabolism. Cytochrome P-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 (cyp2a5(-/-)) mice than in wild-type mice although PPARalpha is elevated in cyp2a5(-/-) mice. To examine why the upregulated PPARalpha failed to prevent the enhanced steatosis in cyp2a5(-/-) mice, we abrogate the upregulated PPARalpha in cyp2a5(-/-) mice by cross-breeding cyp2a5(-/-) mice with PPARalpha knockout (pparalpha(-/-)) mice to create pparalpha(-/-)/cyp2a5(-/-) mice. The pparalpha(-/-)/cyp2a5(-/-) mice, pparalpha(-/-) mice, and cyp2a5(-/-) mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in pparalpha(-/-)/cyp2a5(-/-) mice than in pparalpha(-/-) mice and cyp2a5(-/-) mice. The pparalpha(-/-)/cyp2a5(-/-) mice and pparalpha(-/-) mice exhibited comparable and impaired lipid metabolism. Elevated serum alanine transaminase and liver interleukin-1beta, liver inflammatory cell infiltration, and foci of hepatocellular ballooning were observed in pparalpha(-/-)/cyp2a5(-/-) mice but not in pparalpha(-/-) mice and cyp2a5(-/-) mice. In pparalpha(-/-)/cyp2a5(-/-) 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 pparalpha(-/-)/cyp2a5(-/-) mice is associated with steatosis, and CYP2A5 interacts with PPARalpha to participate in regulating steatohepatitis-associated fibrosis. |
