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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Acknowledgments
This work was supported in part by Grant-in-Aid (No. 20590797 to SY, No. 21390234 to SW) and High Technology Research Center Grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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535_2011_500_MOESM1_ESM.ppt
Supplementary Fig. 1 Effect of cyclosporine A and rapamycin on APAP-induced liver injury. (a) Mice were killed at 12 h after APAP treatment. Some wild-type and Atg7-KO mice were injected intraperitoneally with cyclosporine A (10 mg/kg) or rapamycin (5 mg/kg) for 3 days prior to APAP treatment. Serum ALT levels of WT and KO mice were measured. Bars represent mean and SEM (n = 4, *; P < 0.05 vs, WT at 12 h after APAP treatment, **; P < 0.05 vs, KO at 12 h after APAP treatment, by ANOVA on ranks). (PPT 144 kb)
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Igusa, Y., Yamashina, S., Izumi, K. et al. Loss of autophagy promotes murine acetaminophen hepatotoxicity. J Gastroenterol 47, 433–443 (2012). https://doi.org/10.1007/s00535-011-0500-0
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DOI: https://doi.org/10.1007/s00535-011-0500-0