Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease

作者：Nishida Naoshi^*; Yada Norihisa; Hagiwara Satoru; Sakurai Toshiharu; Kitano Masayuki; Kudo Masatoshi

来源：Journal of Gastroenterology and Hepatology, 2016, 31(9): 1646-1653.

DOI：10.1111/jgh.13318

• hepatocarcinogenesis
• methylation
• nonalcoholic steatohepatitis
• oxidative stress
• tumor suppressor gene

Background and AimNon-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.
MethodsLiver 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.
ResultsWe found that aspartate aminotransferase/alanine aminotransferase ratio, the fibrosis-4 index, and serum -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).
ConclusionsPatients 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.

• 出版日期2016-9