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Autophagy alleviates amiodarone-induced hepatotoxicity.

  • Wandrer F Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
  • Frangež Ž Institute of Pharmacology, University of Bern, Bern, Switzerland.
  • Liebig S Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
  • John K Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
  • Vondran F Department of Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
  • Wedemeyer H Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
  • Veltmann C Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
  • Pfeffer TJ Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
  • Shibolet O Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • Schulze-Osthoff K Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
  • Simon HU Institute of Pharmacology, University of Bern, Bern, Switzerland.
  • Bantel H Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany. Bantel.Heike@mh-hannover.de.
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  • 2020-07-12
Published in:
  • Archives of toxicology. - 2020
Amiodarone
Apoptosis
Autophagy
Drug-induced liver injury
ER stress
Keratin-18
English 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.
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  • English
Open access status
hybrid
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https://folia.unifr.ch/global/documents/284702
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