Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease

Abstract

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.

In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease

“…Caspase-3 activation and hepatocyte apoptosis have been shown to be prominent features of different experimental models of NAFLD-as well as human NAFLD-and to correlate with disease severity. 5,13 To determine whether caspase-3-generated CK-18 fragments are also increased in the livers of NAFLD patients, immunohistochemistry using the M30 monoclonal antibody was performed (Fig. 1).…”

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

“…Furthermore, because NEIL1 can initiate repair in single-stranded and bubble structures, the lack of this repair may lead to severe decreases in mitochondrial replication and transcription rates and, thus, an overall disruption of energy homeostasis. The hypothesis that impaired DNA repair capacity of oxidative damage could increase susceptibility to fatty liver disease has previously been proposed by the Diehl group (33). They demonstrated that the greatest accumulation of 8-oxoguanine lesions and the greatest amount of hepatocyte cell death occurred in their models in which the levels of MYH, the glycosylase responsible for initiating the removal of adenine in the A⅐8-oxoguanine mispair, was the least.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…This would have the effect to compromise the functioning of the oxidative phosphorylation system as a result of the loss of mitochondrial gene products that make up segments of the respiratory chain; subsequently leading to more ROS production. This concept is supported by observations of significant mtDNA mutations and abnormalities in NASH patients [67,68] and in an animal model of fatty liver disease [60]. Whether these mtDNA defects translate into decreased activity and content of the respiratory complexes in obesity induced fatty liver disease is not known.…”

“…More importantly, the molecular mechanisms responsible for oxidant production in obesity induced fatty liver are not known, especially because mitochondrial un-coupling has been shown in experimental models of NAFLD [51]. Studies using liver mitochondria from ob/ob mice have however demonstrated increased O 2 • − compared to mitochondria from lean mice [60,61]. Possible mechanisms for enhanced mitochondrial ROS production include molecular defects within Complexes I and III, as well as increases in RLS, and TNFα mediated ceramide [22,59,62,63].…”