title: Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC). Previously, we reported that DNA oxidation induced epigenetic alteration of tumor suppressor genes (TSGs) and contributed to HCC emergence. Here, we examine the associations between clinicopathological characteristics of NAFLD and advanced oxidative DNA damage that is associated with TSG methylation in the NAFLD liver.
  
  
  METHODS
  Liver biopsies from 65 NAFLD patients were analyzed for clinicopathological features and oxidative DNA damage using immunohistochemistry of 8-hydroxydeoxyguanosine (8-OHdG). Abnormal DNA methylation in the promoters of 6 TSGs, HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, and APC, was examined using MethyLight. Associations between clinicopathological characteristics, methylation of TSGs, and accumulation of 8-OHdG were analyzed.
  
  
  RESULTS
  We found that aspartate aminotransferase/alanine aminotransferase ratio, the fibrosis-4 index, and serum α-fetoprotein (AFP) level were associated with degree of 8-OHdG, and AFP was an independent factor among them (P = 0.0271). Regarding pathological findings, hepatocellular ballooning and stage of fibrosis were also associated with oxidative DNA damage (P = 0.0021 and 0.0054); ballooning was an independent risk for detecting high degree of 8-OHdG in hepatocytes (odds ratio 7.38, 95% confidence interval 1.41-49.13, P = 0.0171). Accumulation of methylated TSGs was significantly associated with deposition of 8-OHdG (P = 0.0362).
  
  
  CONCLUSIONS
  Patients with high serum AFP and high degree of ballooning showed accumulation of oxidative DNA damage that could be a seed of DNA methylation responsible for hepatocarcinogenesis. These characteristics could be risk of HCC; such patients require urgent intervention such as lifestyle modification.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan. naoshi@med.kindai.ac.jp.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Yada
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kitano
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: D000509:alpha-Fetoproteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine
keywords: hepatocarcinogenesis; methylation; nonalcoholic steatohepatitis; oxidative stress; tumor suppressor gene