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Triglyceride accumulation in macrophages upregulates paraoxonase 2 (PON2) expression via ROS-mediated JNK/c-Jun signaling pathway activation.
MedLine Citation:
PMID:  23047827     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The aim of this study was to analyze the effect and mechanism of action of macrophage triglyceride accumulation on cellular PON2 expression. Incubation of J774A.1 (murine macrophages) with VLDL (0-75 μg protein/mL) significantly and dose-dependently increased cellular triglyceride mass, and reactive oxygen species (ROS) formation, by up to 3.3- or 1.8-fold, respectively. PON2 expression (mRNA, protein, activity) in cells treated with VLDL (50 μg protein/mL) was higher by 2- to 3-fold, as compared with control cells. Similar effects were noted upon using THP-1 (human macrophages). Incubation of macrophages with synthetic triglyceride or triglyceride fraction from carotid lesion resulted in similar effects, as shown for VLDL. Upon using specific inhibitors of MEK1/2 (UO126, 10 μM), p38 (SB203580, 10 μM), or JNK (SP600125, 20 μM), we demonstrated that MEK, as well as JNK, but not p38, are involved in VLDL-induced macrophage PON2 upregulation. VLDL activated JNK (but not ERK), which resulted in c-Jun phosphorylation. This signaling pathway is probably activated by ROS, since the antioxidant reduced glutathione (GSH), significantly decreased VLDL-induced macrophage ROS formation, c-Jun phosphorylation and PON2 overexpression. We conclude that macrophage triglyceride accumulation upregulates PON2 expression via MEK/ JNK/c-Jun pathway, and these effects could be related, at least in part, to cellular triglycerides-induced ROS formation. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
Authors:
Mira Rosenblat; Nina Volkova; Nicole Paland; Michael Aviram
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-10
Journal Detail:
Title:  BioFactors (Oxford, England)     Volume:  -     ISSN:  1872-8081     ISO Abbreviation:  Biofactors     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807441     Medline TA:  Biofactors     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.
Affiliation:
The Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
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