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Impeding DNA Polymerase β Activity by Oleic Acid to Inhibit Base Excision Repair and Induce Mitochondrial Dysfunction
Meina Wang1,2, Yannan Qi1, Yu Zhou1
1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
Abstract:
Free fatty acids (FFAs) hepatic accumulation and the resulting oxidative stress contribute to several chronic liver diseases including nonalcoholic steatohepatitis. However, the underlying pathological mechanisms remain unclear. In this study, we propose a novel mechanism whereby the toxicity of FFAs detrimentally affects DNA repair activity. Specifically, we have discovered that oleic acid (OA), a prominent dietary free fatty acid, inhibits the activity of DNA polymerase β (Pol β), a crucial enzyme involved in base excision repair (BER), by actively competing with 2'-deoxycytidine-5'-triphosphate. Consequently, OA hinders the efficiency of BER, leading to the accumulation of DNA damage in hepatocytes overloaded with FFAs. Additionally, the excessive presence of both OA and palmitic acid (PA) lead to mitochondrial dysfunction in hepatocytes. These findings suggest that the accumulation of FFAs hampers Pol β activity and contributes to mitochondrial dysfunction, shedding light on potential pathogenic mechanisms underlying FFAs-related diseases.
Insights
Free fatty acids (FFAs) impair DNA repair by inhibiting DNA polymerase beta (Pol β) activity. This leads to DNA damage and mitochondrial dysfunction, contributing to liver disease pathogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Free fatty acids (FFAs) accumulation in the liver is linked to chronic liver diseases like nonalcoholic steatohepatitis.
- Oxidative stress from FFAs contributes to liver pathology, but underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the novel mechanism by which FFAs induce toxicity in hepatocytes.
- To elucidate the impact of FFAs on DNA repair activity and mitochondrial function.
Main Methods:
- Investigated the effect of oleic acid (OA), a common FFA, on DNA polymerase beta (Pol β) activity in vitro.
- Assessed the impact of OA and palmitic acid (PA) on DNA damage and mitochondrial function in hepatocytes.
Main Results:
- Oleic acid (OA) was found to inhibit DNA polymerase beta (Pol β) activity by competing with 2'-deoxycytidine-5'-triphosphate.
- OA significantly hindered base excision repair (BER) efficiency, causing DNA damage accumulation in FFA-overloaded hepatocytes.
- Excessive OA and palmitic acid (PA) induced mitochondrial dysfunction in hepatocytes.
Conclusions:
- FFA accumulation negatively impacts DNA repair by inhibiting Pol β, a key enzyme in base excision repair (BER).
- FFA-induced DNA damage and mitochondrial dysfunction are potential pathogenic mechanisms in liver diseases.
- This study reveals a novel link between FFAs, DNA repair inhibition, and liver disease progression.
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