Role of autophagy in amiodarone-mediated hepatotoxicity

Question Amiodarone, a widely used antiarrhythmic drug, can cause steatohepatitis, liver fibrosis and cirrhosis. The molecular mechanisms of amiodarone-mediated liver injury remain largely unknown. We therefore investigated amiodarone-mediated hepatocellular injury in patients with chronic heart failure, in primary hepatocytes and HepG2 cells.

Methods The apoptosis biomarker, caspase-cleaved keratin-18, was measured by ELISA in sera from chronic heart failure patients treated with or without amiodarone. Caspase activation was further analyzed in amiodarone-treated hepatocytes by western blotting and enzyme assays. Cell death was assessed by using a cell viability assay. Amiodarone-induced hepatocyte steatosis was detected by triglyceride staining and mRNA expression analyses of lipogenic factors. ER stress and autophagy were analyzed by western blotting of marker proteins.

Results Amiodarone-treated patients with chronic heart failure revealed significantly higher serum levels of caspase-cleaved keratin-18 compared to heathy individuals or patients not receiving amiodarone. We could demonstrate increased apoptosis in hepatocytes treated with amiodarone which was associated with lipid accumulation and ER-stress induction. Hepatocyte steatosis was accompanied by enhanced de novo lipogenesis which, after reaching peak levels, declined together with reduced ER stress. The decrease of amiodarone-mediated lipotoxicity was associated with protective autophagy induction. Vice versa, in hepatocytes treated with the autophagy inhibitor chloroquine as well as in autophagy gene (ATG5 or ATG7)-deficient hepatocytes, amiodarone-mediated toxicity was increased.

Conclusions Amiodarone induces lipid accumulation associated with ER stress and apoptosis in hepatocytes, which is mirrored by increased serum levels of caspase-cleaved keratin-18 in amiodarone-treated patients. Autophagy counteracts this amiodarone-triggered lipotoxicity and could provide a therapeutic strategy for protection from drug-induced liver injury.

Publication History

Article published online:
04 January 2021