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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 2
Li, H2 2
Zhou, Z1
Lam, KSL2 2
Xiao, Y1
Wu, D3
Ding, K3
Wang, Y2 2
Vanhoutte, PM2 2
Xu, A2 2 2
 
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