title: The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease.
abstract: Steatoapoptosis is a hallmark of non-alcoholic fatty liver disease (NAFLD) and is an important factor in liver disease progression. We hypothesized that increased reactive oxygen species resulting from excess dietary fat contribute to liver disease by causing DNA damage and apoptotic cell death, and tested this by investigating the effects of feeding mice high fat or standard diets for 8 weeks. High fat diet feeding resulted in increased hepatic H 2O 2, superoxide production, and expression of oxidative stress response genes, confirming that the high fat diet induced hepatic oxidative stress. High fat diet feeding also increased hepatic steatosis, hepatitis and DNA damage as exemplified by an increase in the percentage of 8-hydroxyguanosine (8-OHG) positive hepatocytes in high fat diet fed mice. Consistent with reports that the DNA damage checkpoint kinase Ataxia Telangiectasia Mutated (ATM) is activated by oxidative stress, ATM phosphorylation was induced in the livers of wild type mice following high fat diet feeding. We therefore examined the effects of high fat diet feeding in Atm-deficient mice. The prevalence of apoptosis and expression of the pro-apoptotic factor PUMA were significantly reduced in Atm-deficient mice fed the high fat diet when compared with wild type controls. Furthermore, high fat diet fed Atm (-/-)  mice had significantly less hepatic fibrosis than Atm (+/+)  or Atm (+/-)  mice fed the same diet. Together, these data demonstrate a prominent role for the ATM pathway in the response to hepatic fat accumulation and link ATM activation to fatty liver-induced steatoapoptosis and fibrosis, key features of NAFLD progression.
authors.affiliation: Center for Animal Resources and Education; Cornell University; Ithaca, NY, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Daugherity
authors.forename: Gabriel
authors.initials: G
authors.lastname: Balmus
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al Saei
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Moore
authors.forename: Delbert
authors.initials: D
authors.lastname: Abi Abdallah
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Maurer
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C488588:PUMA protein, mouse; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D006151:Guanosine; C046215:8-hydroxyguanosine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases