Impeding DNA Polymerase β activity by oleic acid to inhibit base excision repair and induce mitochondrial dysfunction in hepatic cells

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. Here, we present a novel mechanism by which FFAs toxicity negatively affects DNA repair activity. Specifically, we found 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 OA and palmitic acid leads 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.