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Article: Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice

TitlePharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice
Authors
KeywordsNon-alcoholic steatohepatitis
Kupffer cells
Inflammation
Obesity
Issue Date2013
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Journal of Hepatology, 2013, v. 58 n. 2, p. 358-364 How to Cite?
AbstractBackground & Aims: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice. Methods: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR. Results: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice. Conclusions: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/181060
ISSN
2015 Impact Factor: 10.59
2015 SCImago Journal Rankings: 4.570
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHoo, RLCen_US
dc.contributor.authorLee, PCen_US
dc.contributor.authorZhou, Men_US
dc.contributor.authorWong, YLen_US
dc.contributor.authorHui, Xen_US
dc.contributor.authorXu, Aen_US
dc.contributor.authorLam, KSLen_US
dc.date.accessioned2013-02-19T11:32:49Z-
dc.date.available2013-02-19T11:32:49Z-
dc.date.issued2013en_US
dc.identifier.citationJournal of Hepatology, 2013, v. 58 n. 2, p. 358-364en_US
dc.identifier.issn0168-8278en_US
dc.identifier.urihttp://hdl.handle.net/10722/181060-
dc.description.abstractBackground & Aims: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice. Methods: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR. Results: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice. Conclusions: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.-
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhepen_US
dc.relation.ispartofJournal of Hepatologyen_US
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in <Journal title>. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in PUBLICATION, [VOL#, ISSUE#, (DATE)] DOI#en_US
dc.subjectNon-alcoholic steatohepatitis-
dc.subjectKupffer cells-
dc.subjectInflammation-
dc.subjectObesity-
dc.titlePharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in miceen_US
dc.typeArticleen_US
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0168-8278&volume=58&issue=2&spage=358&epage=364&date=2013&atitle=Pharmacological+inhibition+of+adipocyte+fatty+acid+binding+protein+alleviates+both+acute+liver+injury+and+non-alcoholic+steatohepatitis+in+miceen_US
dc.identifier.emailHoo, RLC: rubyhoo@hkucc.hku.hken_US
dc.identifier.emailLee, PC: idalee@hku.hken_US
dc.identifier.emailHui, X: hannahui@hkucc.hku.hken_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_US
dc.identifier.emailLam, KSL: ksllam@hku.hken_US
dc.identifier.authorityHoo, RLC=rp01334en_US
dc.identifier.authorityXu, A=rp00485en_US
dc.identifier.authorityLam, KSL=rp00343en_US
dc.identifier.doi10.1016/j.jhep.2012.10.022-
dc.identifier.pmid23108115-
dc.identifier.scopuseid_2-s2.0-84872388467-
dc.identifier.hkuros213320en_US
dc.identifier.hkuros228176-
dc.identifier.volume58en_US
dc.identifier.issue2en_US
dc.identifier.spage358en_US
dc.identifier.epage364en_US
dc.identifier.isiWOS:000315069900023-

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