title: Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice.
abstract: OBJECTIVE
  Hepatic excessive iron may play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Nrf2 is a master regulator of antioxidative responses. However, the role of Nrf2 in lipid and iron homeostasis remains unclear. Accordingly, it was examined how Nrf2 regulates lipid-related and iron-regulatory genes after feeding a high-fat diet (HFD) with iron.
  
  
  METHODS
  Wild-type and Nrf2-null mice were fed the following diets: (i) control diet (4% soybean oil) for 12 weeks, (ii) control diet for 8 weeks followed by control diet containing 0.5% carbonyl iron for 4 weeks, (iii) HFD (4% soybean oil and 16% lard) for 12 weeks, (iv) HFD for 8 weeks followed by HFD containing 0.5% carbonyl iron for 4 weeks. Blood and livers were removed after 12 weeks.
  
  
  RESULTS
  Nrf2-null control mice exhibited a tendency towards higher hepatic triglycerides compared to wild-type control mice. Hepatic malondialdehyde was higher and hepatic iron levels tended to be higher in Nrf2-null mice than wild-type counterparts while on a HFD. The HFD with iron synergistically induced mRNA expression of Pparα targets, including Acox and Cpt1 in wild-type mice, yet the induction was diminished in Nrf2-null mice. Hepatic hepcidin and ferroportin 1 mRNA expression were increased in wild-type mice after feeding a HFD with iron, but were unchanged in any group of Nrf2-null mice.
  
  
  CONCLUSIONS
  Nrf2 deletion dysregulates hepatic mRNA expression of β-oxidation enzymes and iron-related genes, possibly causing a trend for increased hepatic triglyceride and iron concentrations. Nrf2 may have roles in the progression of NASH.
authors.affiliation: Department of Clinical Laboratory Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan. ytanaka@med.kindai.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takanori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Kamisako
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D064451:Hepcidins; D007501:Iron / Q000097:blood / Q000378:metabolism*; D054354:Iron Carbonyl Compounds / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D004041:Dietary Fats; C579599:Hamp protein, mouse; D064451:Hepcidins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; D014280:Triglycerides; D000098742:Ferroportin; D054354:Iron Carbonyl Compounds; D008315:Malondialdehyde; D002784:Cholesterol; D007501:Iron; D010088:Oxidoreductases; C576471:Acox2 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D002334:Carnitine O-Palmitoyltransferase