Autophagy alleviates amiodarone-induced hepatotoxicity
- PDF / 1,265,681 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 12 Downloads / 220 Views
ORGAN TOXICITY AND MECHANISMS
Autophagy alleviates amiodarone‑induced hepatotoxicity Franziska Wandrer1 · Živa Frangež2 · Stephanie Liebig1 · Katharina John1 · Florian Vondran3 · Heiner Wedemeyer1 · Christian Veltmann4 · Tobias J. Pfeffer4 · Oren Shibolet5 · Klaus Schulze‑Osthoff6 · Hans‑Uwe Simon2,7 · Heike Bantel1 Received: 21 May 2020 / Accepted: 30 June 2020 © The Author(s) 2020
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. Keywords Amiodarone · Apoptosis · Autophagy · ER stress · Drug-induced liver injury · Keratin-18
* Heike Bantel Bantel.Heike@mh‑hannover.de 1
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl‑Neuberg‑Strasse 1, 30625 Hannover, Germany
2
Institute of Pharmacology, University of Bern, Bern, Switzerland
3
Department of Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
4
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
5
Department of Gastroenterology and Hepatology, Tel‑Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel‑Aviv, Israel
6
Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
7
Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia
Abbreviations ALT Alanine aminotransferase AST Aspartate aminotransferase DILI Drug-induced liver injury K18 Keratin-18 NAFLD Non-alcoholic fatty liver disease NASH Non-alcoholic steatohepatitis PHH Primary human hepatocyte RLU Relat
Data Loading...
