scholarly journals Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease

2020 ◽  
Vol 289 (1) ◽  
pp. 84-96 ◽  
Author(s):  
C. J. Pirola ◽  
M. Garaycoechea ◽  
D. Flichman ◽  
G. O. Castaño ◽  
S. Sookoian
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Liver Disease ◽  
Genetic Variability ◽  
Fatty Liver ◽  
Cytochrome B ◽  
Fatty Liver Disease ◽  
Mitochondrial Dna Damage

578 OXIDATIVE DNA DAMAGE LEADING TO MITOCHONDRIAL DNA DEPLETION AGGRAVATES PEDIATRIC NONALCOHOLIC FATTY LIVER DISEASE (PNAFLD)

2021 ◽  
Vol 160 (6) ◽  
pp. S-113
Author(s):  
Preeti Viswanathan ◽  
Luka Maisuradze ◽  
Tatyana Tchaikovskaya ◽  
Bryan Rudolph ◽  
Michelle Ewart ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Oxidative Dna Damage ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Dna Depletion

scholarly journals Oxidative Stress and Nonalcoholic Fatty Liver Disease in Hemodialysis Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Po-Jung Wu ◽  
Jin-Bor Chen ◽  
Wen-Chin Lee ◽  
Hwee-Yeong Ng ◽  
Shu-Ching Lien ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Cellulose Membrane ◽  
Nonalcoholic Fatty Liver ◽  
Factors Associated ◽  
Copy Numbers

Introduction. Nonalcoholic fatty liver disease (NAFLD) is becoming more common around the world and it may progress to cirrhosis and liver failure, increasing mortality risk. In hemodialysis (HD) patients, NAFLD may be a novel risk factor for their high cardiovascular mortality. Heightened oxidative stress is highly prevalent in HD patients. However, the relationship between oxidative stress and NAFLD in HD patients is not well defined.Methods. We studied seventy-one stable nondiabetic HD patients. Nineteen patients had the diagnosis of NAFLD by ultrasonography. Blood levels of oxidative stress markers were measured in each patient, including thiobarbituric acid reactive substances (TBARS), free thiols, superoxide dismutase (SOD) activities, and glutathione peroxidase (GPx) activity. The copy numbers of mitochondrial DNA (mtDNA) in peripheral leukocytes were also determined. Demographic, biochemistry, and hemogram data were recorded. The two groups of patients were compared in order to determine the factors associated with NAFLD in HD patients.Findings. Compared to those without NAFLD, nondiabetic HD patients with NAFLD had significantly higher mtDNA copy number and GPx levels. The two groups did not differ significantly in dialysis adequacy, hemoglobin, serum calcium, phosphorus, albumin, liver function tests, or lipid profiles. Regression analysis confirmed mtDNA copy numbers and GPx levels as two independent factors associated with NAFLD. Compared to those with polysulfone, patients dialyzed with cellulose membrane have significantly higher levels of TBARS. However, patients with or without NAFLD did not differ in their use of either dialysis membrane.Discussion. Oxidative stress (represented by antioxidant defense, GPx) and mitochondrial DNA copy numbers are independently associated with fatty liver disease in nondiabetic HD patients. The diagnostic and therapeutic implications of this key observation warrant further exploration.

scholarly journals The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease

Cell Cycle ◽  
2012 ◽  
Vol 11 (10) ◽  
pp. 1918-1928 ◽  
Author(s):  
Erin K. Daugherity ◽  
Gabriel Balmus ◽  
Ahmed Al Saei ◽  
Elizabeth S. Moore ◽  
Delbert Abi Abdallah ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Dna Damage Checkpoint ◽  
Alcoholic Fatty Liver ◽  
Checkpoint Protein ◽  
Hepatocellular Apoptosis ◽  
Alcoholic Fatty Liver Disease

Su1797 Mitochondrial DNA Polymorphisms and Protection Against Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease (NAFLD)

2015 ◽  
Vol 148 (4) ◽  
pp. S-1053
Author(s):  
Kianoush Jeiran ◽  
Rohini Mehta ◽  
Munkhzul Otgonsuren ◽  
Aaron B. Koenig ◽  
Zachary D. Goodman ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Dna Polymorphisms ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

2021 ◽  
Author(s):  
Gabriella Assante ◽  
Sriram Chandrasekaran ◽  
Stanley Ng ◽  
Aikaterini Tourna ◽  
Carolina H Chung ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Gene Clusters ◽  
Driver Mutations ◽  
Acetyl Coa ◽  
Network Modelling ◽  
Histone Hyperacetylation

The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker γH2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

Mitochondrial DNA does not contribute to the heritability of non-alcoholic fatty liver disease

Mitochondrion ◽  
2011 ◽  
Vol 11 (1) ◽  
pp. 234-235 ◽  
Author(s):  
Nimantha de Alwis ◽  
Guruprasad Aithal ◽  
Elizabetta Bugianesi ◽  
Julian Leathart ◽  
Gavin Hudson ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

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

2004 ◽  
Vol 287 (5) ◽  
pp. G1070-G1077 ◽  
Author(s):  
Daqing Gao ◽  
Chiming Wei ◽  
Lei Chen ◽  
Jiawen Huang ◽  
Shiqi Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Liver Disease ◽  
Fatty Liver ◽  
Mouse Models ◽  
Fatty Liver Disease ◽  
Oxidative Dna Damage ◽  
Oxidant Stress ◽  
Repair Enzyme ◽  
Hepatocyte Death

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.

Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in non-alcoholic fatty liver disease

2021 ◽  
Author(s):  
Lu Xu ◽  
Jingyang Zhou ◽  
Jinhui Che ◽  
Haihong Wang ◽  
Weizhong Yang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Dna Synthesis ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Inflammasome Activation ◽  
High Fat ◽  
Related Proteins ◽  
Mitochondrial Dna Synthesis

Nonalcoholic fatty liver disease (NAFLD) is typified by accumulating excess liver triacylglycerol, inflammation, and liver dysfunction. This study was aimed to investigate the role of mitochondrial DNA synthesis-induced activation of Absent in melanoma 2 (AIM2) inflammasome and pyroptosis in NAFLD. Mice were raised on a high-fat diet for 24 weeks to establish NAFLD models. F4/80 immunofluorescence was performed to reflect the inflammatory response in the liver of mice. Western blot, ELISA, and immunofluorescence were adopted to determine the expression of AIM2 inflammasome-related proteins and factors. EdU immunofluorescence was applied for the examination of mitochondrial DNA expression and flow cytometry for cell pyroptosis. Agarose gel electrophoresis was used to detect the integrity of extracted mouse mitochondrial DNA (mtDNA). The levels of AIM2 inflammasome-related proteins in the liver and the levels of IL-1β and IL-18 in serum were elevated in high-fat diet-induced NAFLD mice. AIM2 inflammasome activation and pyroptosis were triggered, and suppressed activation of AIM2 inflammasome alleviated the inflammation and pyroptosis in the liver of NAFLD mice. Mitochondria were severely damaged and mtDNA was synthesized after NAFLD modeling. Further, mtDNA treatment could promote palmitate (PA)-induced activation of AIM2 inflammasome and pyroptosis. Moreover, inhibition of IRF1 gene alleviated PA-induced AIM2 inflammasome activation and pyroptosis. In conclusion, mitochondrial DNA synthesis could enable AIM2 inflammasome activation and induce the hepatocyte pyroptosis, thereby exacerbating NAFLD.

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