Document Detail


The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease.
MedLine Citation:
PMID:  22544329     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Erin K Daugherity; Gabriel Balmus; Ahmed Al Saei; Elizabeth S Moore; Delbert Abi Abdallah; Arlin B Rogers; Robert S Weiss; Kirk J Maurer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-06-01     Completed Date:  2012-09-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1918-28     Citation Subset:  IM    
Affiliation:
Center for Animal Resources and Education; Cornell University; Ithaca, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Apoptosis Regulatory Proteins / metabolism
Cell Cycle Proteins / deficiency,  genetics,  metabolism*
DNA Damage
DNA-Binding Proteins / deficiency,  genetics,  metabolism*
Diet, High-Fat
Disease Models, Animal
Fatty Liver / metabolism*,  pathology
Fibrosis
Guanosine / analogs & derivatives,  metabolism
Liver / pathology*
Mice
Mice, Knockout
Oxidative Stress
Phosphorylation
Protein-Serine-Threonine Kinases / deficiency,  genetics,  metabolism*
Reactive Oxygen Species / metabolism
Tumor Suppressor Proteins / deficiency,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
K08 DK077728/DK/NIDDK NIH HHS; R01 CA108773/CA/NCI NIH HHS; R01 CA108773/CA/NCI NIH HHS; R03 HD058220/HD/NICHD NIH HHS; R03 HD058220/HD/NICHD NIH HHS; S10 RR023781/RR/NCRR NIH HHS; S10RR023781/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/PUMA protein, mouse; 0/Reactive Oxygen Species; 0/Tumor Suppressor Proteins; 118-00-3/Guanosine; 3868-31-3/8-hydroxyguanosine; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein
Comments/Corrections

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