Autophagy alleviates amiodarone-induced hepatotoxicity.

Wandrer, Franziska; Frangež, Živa; Liebig, Stephanie; John, Katharina; Vondran, Florian; Wedemeyer, Heiner; Veltmann, Christian; Pfeffer, Tobias J; Shibolet, Oren; Schulze-Osthoff, Klaus; Simon, Hans-Uwe; Bantel, Heike (2020). Autophagy alleviates amiodarone-induced hepatotoxicity. Archives of toxicology, 94(10), pp. 3527-3539. Springer-Verlag 10.1007/s00204-020-02837-9

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Frangez, Ziva

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0340-5761

Publisher:

Springer-Verlag

Language:

English

Submitter:

Celine Joray

Date Deposited:

30 Mar 2021 15:32

Last Modified:

30 Mar 2021 15:32

Publisher DOI:

10.1007/s00204-020-02837-9

PubMed ID:

32651653

Uncontrolled Keywords:

Amiodarone Apoptosis Autophagy Drug-induced liver injury ER stress Keratin-18

BORIS DOI:

10.48350/146612

URI:

https://boris.unibe.ch/id/eprint/146612

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