Abstract
Amiodarone 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.
Highlights
Drug-induced liver injury (DILI) represents a major cause of liver failure and liver transplantation in western countries (Chalasani et al 2015)
In initial experiments we asked whether amiodarone treatment of patients with chronic heart failure results in apoptotic liver injury
Using a specific enzyme-linked immunosorbent assay (ELISA) (Fig. 1b), we interestingly found that heart failure patients receiving amiodarone revealed significantly higher serum levels of caspase-cleaved K18 (n = 6; 293.6 ± 58.4 U/L) compared to patients without amiodarone therapy (n = 9; 172.1 ± 17.9 U/L) or healthy control individuals (n = 13; 174.8 ± 14.0 U/L)
Summary
Drug-induced liver injury (DILI) represents a major cause of liver failure and liver transplantation in western countries (Chalasani et al 2015). Drug-induced lipid accumulation in the liver is caused by increased de novo lipogenesis, reduced very low density lipoprotein secretion and/or drug-mediated mitochondrial dysfunction leading to impaired β-oxidation of fatty acids. Mitochondrial dysfunction further leads to increased production of reactive oxygen species (ROS) which elicits the peroxidation of fatty acids and the generation of pro-inflammatory cytokines. These events trigger the induction of steatohepatitis with the risk of developing liver fibrosis and cirrhosis (Begriche et al 2011)
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