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01-04-2012 | Original Article—Liver, Pancreas, and Biliary Tract

Loss of autophagy promotes murine acetaminophen hepatotoxicity

Authors: Yuki Igusa, Shunhei Yamashina, Kousuke Izumi, Yoshihiro Inami, Hiroo Fukada, Masaaki Komatsu, Keiji Tanaka, Kenichi Ikejima, Sumio Watanabe

Published in: Journal of Gastroenterology | Issue 4/2012

Abstract

Background

Previous reports indicate that mitochondrial dysfunction is essential for the development of liver injury due to acetaminophen. On the other hand, autophagy, which is a major catabolic pathway, plays a critical role in removing protein aggregates, as well as damaged or excess mitochondria in order to maintain intracellular homeostasis. The aim of this study was to clarify if autophagy is linked to liver injury due to acetaminophen.

Methods

Acetaminophen was administered intraperitoneally to liver-specific Atg7-deficient mice and wild-type mice. A variety of cellular and molecular approaches were used to evaluate the role of autophagy in acetaminophen-induced cell death.

Results

Treatment with acetaminophen induced formation of autophagosomes in hepatocytes from wild-type mice, but not in Atg7-deficient mice. Autophagy deficiency enhanced acetaminophen-induced liver injury and activation of caspase-3 and -7 in the liver. Acetaminophen-induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, and JNK activation in hepatocytes were accelerated by autophagy deficiency. The combination of cyclosporin A or JNK inhibitor (SP600125) with acetaminophen blunted both acetaminophen-induced apoptotic and necrotic cell death in autophagy-deficient hepatocytes.

Conclusions

Induction of autophagy during acetaminophen treatment plays a pivotal role in the protection against acetaminophen-induced hepatotoxicity through the removal of damaged mitochondria and oxidative stress.

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Title: Loss of autophagy promotes murine acetaminophen hepatotoxicity
Authors: Yuki Igusa
Shunhei Yamashina
Kousuke Izumi
Yoshihiro Inami
Hiroo Fukada
Masaaki Komatsu
Keiji Tanaka
Kenichi Ikejima
Sumio Watanabe
Publication date: 01-04-2012
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 4/2012
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-011-0500-0

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Abstract

Background

Methods

Results

Conclusions

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