RRC ID 27914
Author Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX.
Title Activation of autophagy protects against acetaminophen-induced hepatotoxicity.
Journal Hepatology
Abstract UNLABELLED:Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria-damage-induced cell death. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP-induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP-induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP-induced autophagy was suppressed by N-acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP-induced autophagy. Pharmacological inhibition of autophagy by 3-methyladenine or chloroquine further exacerbated APAP-induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP-induced hepatotoxicity.
CONCLUSION:APAP overdose induces autophagy, which attenuates APAP-induced liver cell death by removing damaged mitochondria.
Volume 55(1)
Pages 222-32
Published 2012-1-1
DOI 10.1002/hep.24690
PMID 21932416
PMC PMC3245329
MeSH Acetaminophen / toxicity* Acetylcysteine / pharmacology Adenine / analogs & derivatives Adenine / pharmacology Analgesics, Non-Narcotic / toxicity* Animals Autophagy / drug effects Autophagy / physiology* Chemical and Drug Induced Liver Injury / drug therapy Chemical and Drug Induced Liver Injury / metabolism Chemical and Drug Induced Liver Injury / pathology* Free Radical Scavengers / pharmacology Green Fluorescent Proteins / genetics Hepatocytes / metabolism Hepatocytes / pathology* Mice Mice, Inbred C57BL Mice, Transgenic Primary Cell Culture TOR Serine-Threonine Kinases / metabolism
IF 14.679
Times Cited 227
Mice RBRC00806