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Article: Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH 2-terminal kinases and activator protein-1
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TitleAdipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH 2-terminal kinases and activator protein-1
 
AuthorsHui, X2
Li, H2
Zhou, Z1
Lam, KSL2
Xiao, Y1
Wu, D3
Ding, K3
Wang, Y2
Vanhoutte, PM2
Xu, A2
 
Issue Date2010
 
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
CitationJournal Of Biological Chemistry, 2010, v. 285 n. 14, p. 10273-10280 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M109.097907
 
AbstractAdipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in A-FABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
 
ISSN0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
DOIhttp://dx.doi.org/10.1074/jbc.M109.097907
 
PubMed Central IDPMC2856232
 
ISI Accession Number IDWOS:000276264600011
Funding AgencyGrant Number
Research Grants Council of Hong Kong
National Natural Science Foundation of ChinaN_HKU 735/08
30831160518
Collaborative Research FundHKU 2/07C
Funding Information:

This work was supported by Research Grants Council of Hong Kong, the National Natural Science Foundation of China Joint Research Scheme (Projects N_HKU 735/08 and 30831160518), and the Collaborative Research Fund (HKU 2/07C) from the Research Grants Council of Hong Kong.

 
ReferencesReferences in Scopus
 
GrantsVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention
Adipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications
 
DC FieldValue
dc.contributor.authorHui, X
 
dc.contributor.authorLi, H
 
dc.contributor.authorZhou, Z
 
dc.contributor.authorLam, KSL
 
dc.contributor.authorXiao, Y
 
dc.contributor.authorWu, D
 
dc.contributor.authorDing, K
 
dc.contributor.authorWang, Y
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorXu, A
 
dc.date.accessioned2011-03-21T08:59:32Z
 
dc.date.available2011-03-21T08:59:32Z
 
dc.date.issued2010
 
dc.description.abstractAdipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in A-FABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationJournal Of Biological Chemistry, 2010, v. 285 n. 14, p. 10273-10280 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M109.097907
 
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M109.097907
 
dc.identifier.epage10280
 
dc.identifier.hkuros178258
 
dc.identifier.isiWOS:000276264600011
Funding AgencyGrant Number
Research Grants Council of Hong Kong
National Natural Science Foundation of ChinaN_HKU 735/08
30831160518
Collaborative Research FundHKU 2/07C
Funding Information:

This work was supported by Research Grants Council of Hong Kong, the National Natural Science Foundation of China Joint Research Scheme (Projects N_HKU 735/08 and 30831160518), and the Collaborative Research Fund (HKU 2/07C) from the Research Grants Council of Hong Kong.

 
dc.identifier.issn0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
dc.identifier.issue14
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2856232
 
dc.identifier.pmid20145251
 
dc.identifier.scopuseid_2-s2.0-77951232674
 
dc.identifier.spage10273
 
dc.identifier.urihttp://hdl.handle.net/10722/132182
 
dc.identifier.volume285
 
dc.languageeng
 
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Biological Chemistry
 
dc.relation.projectVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention
 
dc.relation.projectAdipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications
 
dc.relation.referencesReferences in Scopus
 
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.
 
dc.subject.meshFatty Acid-Binding Proteins - physiology
 
dc.subject.meshInflammation - immunology - metabolism
 
dc.subject.meshJNK Mitogen-Activated Protein Kinases - genetics - metabolism
 
dc.subject.meshMacrophages - metabolism
 
dc.subject.meshTranscription Factor AP-1 - genetics - metabolism
 
dc.titleAdipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH 2-terminal kinases and activator protein-1
 
dc.typeArticle
 
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Author Affiliations
  1. Second Xiangya Hospital of Central-South University
  2. The University of Hong Kong
  3. Chinese Academy of Sciences