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Autophagy alleviates amiodarone-induced hepatotoxicity

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502042/
https://www.ncbi.nlm.nih.gov/pubmed/32651653
http://dx.doi.org/10.1007/s00204-020-02837-9
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author 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
author_facet 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
author_sort Wandrer, Franziska
collection PubMed
description 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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spelling pubmed-75020422020-10-01 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 Arch Toxicol Organ Toxicity and Mechanisms 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. Springer Berlin Heidelberg 2020-07-10 2020 /pmc/articles/PMC7502042/ /pubmed/32651653 http://dx.doi.org/10.1007/s00204-020-02837-9 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Organ Toxicity and Mechanisms
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
Autophagy alleviates amiodarone-induced hepatotoxicity
title Autophagy alleviates amiodarone-induced hepatotoxicity
title_full Autophagy alleviates amiodarone-induced hepatotoxicity
title_fullStr Autophagy alleviates amiodarone-induced hepatotoxicity
title_full_unstemmed Autophagy alleviates amiodarone-induced hepatotoxicity
title_short Autophagy alleviates amiodarone-induced hepatotoxicity
title_sort autophagy alleviates amiodarone-induced hepatotoxicity
topic Organ Toxicity and Mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502042/
https://www.ncbi.nlm.nih.gov/pubmed/32651653
http://dx.doi.org/10.1007/s00204-020-02837-9
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