Akt and ERK/Nrf2 activation by PUFA oxidation-derived aldehydes upregulates FABP4 expression in human macrophages.
OBJECTIVE
In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation.


RESULTS
Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter.


CONCLUSIONS
We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis.
Research Unit on Lipids and Atherosclerosis, Internal Medicine Department, Sant Joan University Hospital, IISPV, Universitat Rovira i Virgili, CIBERDEM, Reus, Spain.
Iolanda
I
Lázaro
Raimon
R
Ferré
Lluís
L
Masana
Anna
A
Cabré
D017667:Adipocytes / Q000166:cytology; D000447:Aldehydes / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry; D050197:Atherosclerosis / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D000447:Aldehydes; D000975:Antioxidants; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D005231:Fatty Acids, Unsaturated; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen
Aldehyde; Atherosclerosis; FABP4; Macrophages; Nrf2