Fatty acid binding protein 4/Ap2-dependent BLT1R expression and signaling

Ann V. Hertzel, Hongliang Xu, Michael Downey, Nicholas Kvalheim, David A. Bernlohr

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Previous studies have shown that reduced levels of the adipocyte fatty acid binding protein (FABP)4 (AFABP/ Ap2), result in metabolic improvement including potentiated insulin sensitivity and attenuated atherosclerosis. Mechanistically, pharmacologic or genetic inhibition of FABP4 in macrophages upregulates UCP2, attenuates reactive oxygen species (ROS) production, polarizes cells toward the anti-inflammatory M2 state, and reduces leukotriene (LT) secretion. At the protein level, FABP4 stabilizes LTA4 toward chemical hydrolysis, thereby potentiating inflammatory LTC4 synthesis. Herein, we extend the FABP4-LT axis and demonstrate that genetic knockout of FABP4 reduces expression of the major macrophage LT receptor, LTB4 receptor 1 (BLT1R), via a ROS-dependent mechanism. Consistent with inflammation driving BLT1R expression, M1 polarized macrophages express increased levels of BLT1R relative to M2 polarized macrophages and treatment with proinflammatory lipopolysaccharide increased BLT1R mRNA and protein expression. In FABP4 knockout macrophages, silencing of UCP2, increased ROS levels and led to increased expression of BLT1R mRNA. Similarly, addition of exogenous H2O2 upregulated BLT1R expression, whereas the addition of a ROS scavenger, N-acetyl cysteine, decreased BLT1R levels. As compared with WT macrophages, LTB4-BLT1R-de-pendent JAK2-phosphorylation was reduced in FABP4 knockout macrophages. In summary, these results indicate that FABP4 regulates the expression of BLT1R and its downstream signaling via control of oxidative stress in macrophages.—Hertzel, A. V., H. Xu, M. Downey, N. Kvalheim, and D. A. Bernlohr. Fatty acid binding protein 4/Ap2-dependent BLT1R expression and signaling.

Original languageEnglish (US)
Pages (from-to)1354-1361
Number of pages8
JournalJournal of lipid research
Volume58
Issue number7
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
The authors would like to thank the members of the Bernlohr laboratory for helpful discussions during the study and preparation of the manuscript. The support of the Minnesota Supercomputing Institute is gratefully acknowledged. This work was supported by National Institutes of Health Grant R01 DK053189 to D.A.B. and the Minnesota Nutrition and Obesity Center (National Institutes of Health Grant P30 DK050456). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Adipocyte myelin P2
  • Inflammation
  • Leukotriene B4 receptor 1
  • Leukotrienes
  • Lipid mediators
  • Lipids
  • Macrophages
  • Signal transduction

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