title: Loss of autophagy promotes murine acetaminophen hepatotoxicity.
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.
authors: Department of Gastroenterology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. yigusa@juntendo.ac.jp
authors: Yuki
authors: Y
authors: Igusa
authors: Shunhei
authors: S
authors: Yamashina
authors: Kousuke
authors: K
authors: Izumi
authors: Yoshihiro
authors: Y
authors: Inami
authors: Hiroo
authors: H
authors: Fukada
authors: Masaaki
authors: M
authors: Komatsu
authors: Keiji
authors: K
authors: Tanaka
authors: Kenichi
authors: K
authors: Ikejima
authors: Sumio
authors: S
authors: Watanabe
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D018929:Cell Culture Techniques; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D005434:Flow Cytometry; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000172:deficiency; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D000071193:Autophagy-Related Protein 7