title: Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice.
abstract: OBJECTIVE
  Acetaminophen (APAP) overdose causes hepatic necrosis and acute liver injury by inducing mitochondrial dysfunction and damage. Although the biochemical pathways that mediate APAP-induced hepatotoxicity have been well studied, the body's defense mechanism to attenuate this disease remains elusive. This study investigated the roles of adiponectin, an adipocyte-secreted adipokine with pleiotropic protective effects against obesity-related metabolic dysfunction, in the pathogenesis of APAP-induced liver injury in mice.
  
  
  METHODS
  Adiponectin knockout (ADN KO) and C57 wild type mice were treated with an overdose of APAP, followed by histological and biochemical evaluation of liver injury and activation of autophagy. The mechanism of adiponectin in APAP-induced hepatocytic toxicity was also explored in primary cultured hepatocytes.
  
  
  RESULTS
  APAP overdose triggers a marked accumulation of adiponectin in injured liver tissues. ADN KO mice exhibit severely exacerbated mitochondrial dysfunction and damage, oxidative stress and necrosis and much higher mortality in response to APAP overdose, whereas these changes are reversed by a single injection of adiponectin. Mechanistically, adiponectin induces autophagosome formation by AMP-activated protein kinase (AMPK)-dependent activation of the Unc-51-like kinase 1, consequently leading to the removal of damaged mitochondria from hepatocytes. The protective effects of adiponectin against APAP-induced mitochondrial damage, oxidative stress and necrosis are abrogated by blockage of AMPK or pharmacological inhibition of autophagy.
  
  
  CONCLUSIONS
  Our findings suggest that the APAP-induced accumulation of adiponectin in liver tissues serves as an adaptive mechanism to ameliorate hepatotoxicity by promoting autophagy-mediated clearance of damaged mitochondria. Adiponectin agonists may represent a promising therapy for the drug-induced acute liver failure.
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Pan
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
authors.forename: Leigang
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Lu
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. Electronic address: amxu@hku.hk.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China. Electronic address: xiaokunli@wzmc.edu.cn.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000082:Acetaminophen / Q000633:toxicity*; D052242:Adiponectin / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D001343:Autophagy / Q000502:physiology; D000071189:Autophagy-Related Protein-1 Homolog; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D019610:Cytoprotection; D062787:Drug Overdose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D052242:Adiponectin; D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Acetaminophen; Acute liver injury; Adiponectin; Autophagy; Mitochondrial dysfunction