Wandrer, FranziskaFranziskaWandrerFrangez, ZivaZivaFrangezLiebig, StephanieStephanieLiebigJohn, KatharinaKatharinaJohnVondran, FlorianFlorianVondranWedemeyer, HeinerHeinerWedemeyerVeltmann, ChristianChristianVeltmannPfeffer, Tobias JTobias JPfefferShibolet, OrenOrenShiboletSchulze-Osthoff, KlausKlausSchulze-OsthoffSimon, Hans-UweHans-UweSimonBantel, HeikeHeikeBantel2024-09-022024-09-022020-10https://boris-portal.unibe.ch/handle/20.500.12422/37167Amiodarone is a widely used antiarrhythmic drug that can cause the development of steatohepatitis as well as liver fibrosis and cirrhosis. The molecular mechanisms of amiodarone-mediated liver injury remain largely unknown. We therefore analyzed amiodarone-mediated hepatocellular injury in patients with chronic heart failure, in primary hepatocytes and HepG2 cells. We found that amiodarone-treated patients with chronic heart failure revealed significantly higher serum levels of caspase-cleaved keratin-18, an apoptosis biomarker, compared to healthy individuals or patients not receiving amiodarone. Furthermore, amiodarone treatment of hepatocytes resulted in apoptosis associated with lipid accumulation and ER-stress induction. Liver cell steatosis was accompanied by enhanced de novo lipogenesis which, after reaching peak levels, declined together with decreased activation of ER stress. The decline of amiodarone-mediated lipotoxicity was associated with protective autophagy induction. In contrast, in hepatocytes treated with the autophagy inhibitor chloroquine as well as in autophagy gene (ATG5 or ATG7)-deficient hepatocytes, amiodarone-triggered toxicity was increased. In conclusion, we demonstrate that amiodarone induces lipid accumulation associated with ER stress and apoptosis in hepatocytes, which is mirrored by increased keratin-18 fragment serum levels in amiodarone-treated patients. Autophagy reduces amiodarone-mediated lipotoxicity and could provide a therapeutic strategy for protection from drug-induced liver injury.enAmiodarone Apoptosis Autophagy Drug-induced liver injury ER stress Keratin-18600 - Technology::610 - Medicine & healtharticle10.48350/1466123265165310.1007/s00204-020-02837-9