Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease.
Mitochondrial generation of reactive oxygen species (ROS) is increased in mice with fatty livers induced by genetic obesity, chronic consumption of ethanol, or methionine/choline-deficient diets. Both nuclear and mitochondrial (mt) DNA are targets for ROS-induced damage and accumulate hydroxylated bases, such as 8-hydroxy-2'-deoxyguanosine (8-oxoG) and base substitution of adenine with 8-oxoG (A*8-oxoG), that introduce mutations that promote cancer as well as cell death. The mammalian homolog of the bacterial DNA mismatch repair enzyme MutY (MYH) removes A*8-oxoG from nuclear and mtDNA, reduces 8-oxoG accumulation, and restores genomic stability after ROS exposure. Cumulative damage to mtDNA occurs as fatty liver disease progresses. Therefore, differences in hepatic MYH activity may influence the severity of fatty liver disease. To evaluate this hypothesis, we compared mtH2O2 production, MYH expression, oxidative DNA damage, and hepatocyte death in healthy mice and different mouse models of fatty liver disease. The results show that diverse causes of steatohepatitis increase mtROS production, limit repair of mtDNA, and oxidatively damage DNA. However, there are important differences in the DNA repair response to oxidant stress among mouse models of fatty liver disease. Independent of the degree of mtROS generation, models with the least MYH exhibit the greatest accumulation of 8-oxoG and the most hepatocyte death. These findings raise the intriguing possibility that inherited or acquired differences in DNA repair enzyme activity may underlie some of the interindividual differences in fatty liver disease outcomes.
Gao
Daqing
D
Department of Surgery, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Wei
Chiming
C
Chen
Lei
L
Huang
Jiawen
J
Yang
Shiqi
S
Diehl
Anna Mae
AM
D000818:Animals; D016923:Cell Death; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*
D006151:Guanosine; C046215:8-hydroxyguanosine; D006861:Hydrogen Peroxide; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D045643:DNA Repair Enzymes