Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways. Academic Article uri icon

Overview

MeSH

  • Animals
  • Atherosclerosis
  • Base Sequence
  • Female
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Macrophages
  • Male
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Sex Factors
  • Signal Transduction
  • Transcription, Genetic

MeSH Major

  • Fatty Acid-Binding Proteins
  • Gene Expression Regulation
  • PPAR gamma
  • Receptors, Glucocorticoid
  • Tamoxifen

abstract

  • Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen.

publication date

  • September 15, 2013

has subject area

  • Animals
  • Atherosclerosis
  • Base Sequence
  • Fatty Acid-Binding Proteins
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Macrophages
  • Male
  • Mice
  • Mice, Knockout
  • PPAR gamma
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid
  • Sex Factors
  • Signal Transduction
  • Tamoxifen
  • Transcription, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1042/BJ20130580

PubMed ID

  • 23805908

Additional Document Info

start page

  • 467

end page

  • 477

volume

  • 454

number

  • 3