title: Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice.
abstract: BACKGROUND
  Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced liver injury. However, its role on liver fibrosis remains unclear. This study aims to elucidate the effect and the mechanism of HO-1 in nutritional fibrosing steatohepatitis in mice.
  
  
  METHODS
  Male C57BL/6J mice were fed with a methionine-choline deficient (MCD) diet for eight weeks to induce hepatic fibrosis. HO-1 chemical inducer (hemin), HO-1 chemical inhibitor zinc protoporphyrin IX (ZnPP-IX) and/or adenovirus carrying HO-1 gene (Ad-HO-1) were administered to mice, respectively. Liver injury was assessed by serum ALT, AST levels and histological examination; hepatic lipid peroxides levels were determined; the expression levels of several fibrogenic related genes were assayed by real-time quantitative PCR and Western blot.
  
  
  RESULTS
  MCD feeding mice showed progressive hepatic injury including hepatic steatosis, inflammatory infiltration and fibrosis. Induction of HO-1 by hemin or Ad-HO-1 significantly attenuated the severity of liver injury. This effect was associated with the up-regulation of HO-1, reduction of hepatic lipid peroxides levels, down-regulation of inflammatory factors tumor necrosis factor-alpha, interleukin-6 and suppressor of cytokine signaling-1 as well as the pro-fibrotic genes alpha-smooth muscle actin, transforming growth factor-β1, matrix metallopeptidase-2 and matrix metallopeptidase-9. A contrary effect was observed in mice treated with ZnPP-IX.
  
  
  CONCLUSIONS
  The present study provided the evidence for the protective role of HO-1 in ameliorating MCD diet-induced fibrosing steatohepatitis. Modulation of HO-1 expression might serve as a therapeutic approach for fibrotic steatohepatitis.
authors.affiliation: Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Rong Qi
authors.initials: RQ
authors.lastname: Wang
authors.forename: Yue Min
authors.initials: YM
authors.lastname: Nan
authors.forename: Wen Juan
authors.initials: WJ
authors.lastname: Wu
authors.forename: Ling Bo
authors.initials: LB
authors.lastname: Kong
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.forename: Su Xian
authors.initials: SX
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Kong
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002796:Choline Deficiency / Q000150:complications; D004790:Enzyme Induction; D005234:Fatty Liver / Q000473:pathology / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006427:Hemin / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000209:etiology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D008054:Lipid Peroxides; D008565:Membrane Proteins; D011524:Protoporphyrins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C017803:zinc protoporphyrin; D008315:Malondialdehyde; D006427:Hemin; D008715:Methionine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9