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

TitleAdiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice.
Authors
Issue Date2014
Citation
Journal of Hepatology, 2014, v. 61 n. 4, p. 825–831 How to Cite?
AbstractBACKGROUND & 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.
Persistent Identifierhttp://hdl.handle.net/10722/203055
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLin, Zen_US
dc.contributor.authorWu, Fen_US
dc.contributor.authorLin, Sen_US
dc.contributor.authorPan, Xen_US
dc.contributor.authorJin, Len_US
dc.contributor.authorLu, Ten_US
dc.contributor.authorShi, Len_US
dc.contributor.authorWang, Yen_US
dc.contributor.authorXu, Aen_US
dc.contributor.authorLi, Xen_US
dc.date.accessioned2014-09-19T11:29:22Z-
dc.date.available2014-09-19T11:29:22Z-
dc.date.issued2014en_US
dc.identifier.citationJournal of Hepatology, 2014, v. 61 n. 4, p. 825–831en_US
dc.identifier.urihttp://hdl.handle.net/10722/203055-
dc.description.abstractBACKGROUND & 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.en_US
dc.languageengen_US
dc.relation.ispartofJournal of Hepatologyen_US
dc.titleAdiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice.en_US
dc.typeArticleen_US
dc.identifier.emailLin, Z: zlin2011@hku.hken_US
dc.identifier.emailWang, Y: yuwanghk@hku.hken_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_US
dc.identifier.authorityWang, Y=rp00239en_US
dc.identifier.authorityXu, A=rp00485en_US
dc.identifier.doi10.1016/j.jhep.2014.05.033en_US
dc.identifier.pmid24882054-
dc.identifier.hkuros235335en_US
dc.identifier.hkuros230295-
dc.identifier.volume61en_US
dc.identifier.isiWOS:000342252200018-

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