Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway.
Atorvastatin (ATO) is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin-induced liver injury. This study investigated mechanisms of ATO-induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase-2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration-dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria-dependent apoptosis as indicated by increased Bax/Bcl-2 ratio, cleaved caspase-3, mitochondrial cytochrome c release and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tert-butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO-induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria-dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO-induced liver injury.
['Li|Li-Zhong|LZ|0000-0002-4252-0595', 'Zhao|Zeng-Ming|ZM|', 'Zhang|Li|L|', 'He|Jun|J|', 'Zhang|Ting-Fen|TF|', 'Guo|Jia-Bin|JB|', 'Yu|Lin|L|', 'Zhao|Jun|J|', 'Yuan|Xiao-Yan|XY|', 'Peng|Shuang-Qing|SQ|']
D017209:Apoptosis D000069059:Atorvastatin D056945:Hep G2 Cells D006801:Humans D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D006937:Hypercholesterolemia D008928:Mitochondria D051267:NF-E2-Related Factor 2
atorvastatin mitochondrial dysfunction apoptosis HepG2 Nrf2 TBHQ