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Activation of autophagy protects against acetaminophen-induced hepatotoxicity.

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.

SUBMITTER: Ni HM

PROVIDER: S-EPMC3245329 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Activation of autophagy protects against acetaminophen-induced hepatotoxicity.

Ni Hong-Min HM Bockus Abigail A Boggess Nikki N Jaeschke Hartmut H Ding Wen-Xing WX

Hepatology (Baltimore, Md.) 20111206 1

<h4>Unlabelled</h4>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 i ...[more]

PMID: 21932416

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Project description:BACKGROUND & AIMS:Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in the US and many other countries. Metabolism of APAP results in formation of APAP protein adducts (APAP-AD) in hepatocytes and triggers mitochondrial dysfunction and necrosis. However, the mechanisms for how APAP-AD are removed from hepatocytes remain unknown. METHODS:Mice or primary hepatocytes were treated with APAP. APAP-AD were determined by immunoblot, immunostaining and high pressure liquid chomatography with electrochemical detection analysis. RESULTS:We found that APAP-AD were detected at 1h, peaked at approximately 2h, declined at 6h and almost full removed at 24h post treatment with APAP in mouse livers and in primary mouse hepatocytes. APAP-AD displayed a punctate pattern and were colocalized with GFP-LC3 positive autophagosomes and Lamp1 positive lysosomes in APAP-treated primary hepatocytes. Moreover, isolated autophagosomes and autolysosomes from APAP-treated mouse livers contained APAP-AD, suggesting autophagy may selectively remove APAP-AD. APAP-AD were detected in both detergent soluble and insoluble pools in APAP-treated mouse livers and hepatocytes. More importantly, pharmacological inhibition of autophagy by leupeptin or chloroquine increased whereas induction of autophagy by Torin 1 decreased serum APAP-AD levels in APAP-treated mice, which correlated with alanine aminotransferase levels and liver necrosis. Furthermore, SQSTM1/p62, an autophagy receptor protein, was recruited to APAP-AD. Adenovirus-mediated shRNA knockdown of SQSTM1/p62 led to increased APAP-AD and necrosis in primary hepatocytes. CONCLUSIONS:Our data indicate that APAP-AD are removed though selective autophagy. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury. LAY SUMMARY:Acetaminophen overdose can form acetaminophen protein adducts and mitochondria damage in hepatocytes resulting in liver injury. Activation of autophagy-lysosomal degradation pathway can help to remove acetaminophen protein adducts. Pharmacological induction of autophagy may be a novel promising approach for treating APAP-induced liver injury.

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Activation of autophagy protects against acetaminophen-induced hepatotoxicity.

Publications

Activation of autophagy protects against acetaminophen-induced hepatotoxicity.

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