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J Hepatol. 2014 Oct;61(4):825-31. doi: 10.1016/j.jhep.2014.05.033. Epub 2014 Jun 2.

Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice.

Author information

  • 1School 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.
  • 2Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China.
  • 3School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
  • 4School 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.
  • 5School 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.
  • 6School 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.

Abstract

BACKGROUND & AIMS:

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.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Acetaminophen; Acute liver injury; Adiponectin; Autophagy; Mitochondrial dysfunction

PMID:
24882054
[PubMed - in process]
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