title: Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. We investigated the role of HO-1 in nutritional steatohepatitis in vitro and in vivo.
  
  
  METHODS
  AML-12 hepatocytes were cultured in methionine- and choline-deficient (MCD) medium. Cells were transfected with an adenovirus vector that expressed HO-1 (Ad-HO-1) or incubated with the HO-1 inducer hemin or the HO-1 inhibitor stannic mesoporphyrin for 24 hours. C57BL6 mice and db/db mice were fed MCD or control diets, with or without hemin, for up to 4 weeks.
  
  
  RESULTS
  AML-12 cells exposed to MCD medium developed significant steatosis, increased release of alanine aminotransferase, and showed signs of oxidative injury. Incubation with hemin induced HO-1 protein, suppressed steatosis, and reduced levels of alanine aminotransferase and lipid peroxidation. A comparable effect was observed in cells transfected with Ad-HO-1, whereas incubation of these cells with stannic mesoporphyrin completely abolished the Ad-HO-1- or hemin-mediated protection of hepatocytes. Mice injected with hemin significantly attenuated MCD-induced steatohepatitis and increased HO-1 protein and activity. This effect was associated with up-regulation of antioxidant chaperones and enzymes, down-regulation of proinflammatory cytokines, and up-regulation of the anti-inflammatory interleukin-22. Moreover, the reduction in steatosis caused by hemin was affected by up-regulation of peroxisome proliferator-activated receptor-alpha and by down-regulation of sterol regulatory element binding protein-1c.
  
  
  CONCLUSIONS
  HO-1 can interrupt progression of nutritional steatohepatitis by inducing an antioxidant pathway, suppressing production of cytokines, and modifying fatty acid turnover. Induction of HO-1 might provide a new approach for treatment of steatohepatitis.
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. junyu@cuhk.edu.hk
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Eagle S H
authors.initials: ES
authors.lastname: Chu
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Wang
authors.forename: Shiyan
authors.initials: S
authors.lastname: Wang
authors.forename: Chung W
authors.initials: CW
authors.lastname: Wu
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Wong
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.forename: Geofferey C
authors.initials: GC
authors.lastname: Farrell
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D008652:Mesoporphyrins; D047493:PPAR alpha; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C031468:mesoporphyrin IX; D006427:Hemin; D008715:Methionine; D051547:Heme Oxygenase-1