title: Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency.
abstract: OBJECTIVE
  Hepatic steatosis is a metabolic liver disease with the potential to progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The aim of this study was to investigate the impact of CCAAT/enhancer-binding protein homologous protein (CHOP) deficiency in the development of steatosis-associated progression of HCC.
  
  
  METHODS
  Eight-week-old wild-type (WT) and CHOP knockout (CHOP-/-) mice were fed a normal or methionine-choline-deficient (MCD) diet. Mice were sacrificed after 3 weeks, and steatosis, inflammation, apoptosis, and liver damage were assessed. We also evaluated fibrosis after 8 weeks of nutrition intervention. To explore the role of CHOP in liver carcinogenesis, 25 mg/kg of diethylnitrosamine (DEN) was injected intraperitoneally into 2-week-old mice, which were then fed the aforementioned diets from 8 to 24 weeks of age. CHOP expression in HCC patient livers was also evaluated.
  
  
  RESULTS
  CHOP deficiency did not affect steatosis but significantly reduced apoptotic cells, inflammation scores, and serum liver enzymes. It also significantly suppressed total serum bilirubin levels, fibrotic area size, and messenger RNA expression of profibrotic cytokines. DEN-initiated carcinogenesis was promoted by the MCD diet, while CHOP deficiency significantly attenuated the total number and maximum diameter of tumors and the Ki-67 labeling index. In human livers, CHOP expression was enhanced in parallel with non-alcoholic steatohepatitis-to-HCC progression.
  
  
  CONCLUSIONS
  CHOP deficiency attenuated apoptosis, inflammation, fibrosis, and tumorigenesis under fat-loading conditions, indicating that a therapeutic strategy targeting CHOP might be effective for fat-induced liver injury and protecting against promotion of carcinogenesis in patients with liver steatosis.
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kan
authors: K
authors: Toriguchi
authors: Etsuro
authors: E
authors: Hatano
authors: Kazutaka
authors: K
authors: Tanabe
authors: Kenji
authors: K
authors: Takemoto
authors: Kojiro
authors: K
authors: Nakamura
authors: Yukinori
authors: Y
authors: Koyama
authors: Satoru
authors: S
authors: Seo
authors: Kojiro
authors: K
authors: Taura
authors: Shinji
authors: S
authors: Uemoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000628:therapy*; D002796:Choline Deficiency; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D008297:Male; D008715:Methionine / Q000172:deficiency*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058990:Molecular Targeted Therapy
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D008715:Methionine
keywords: CCAAT/enhancer-binding protein homologous protein; hepatocellular carcinoma; nonalcoholic steatohepatitis