Tamoxifen inhibits macrophage FABP4 expression through the combined effects of GR and PPAR{gamma} pathways

In this study, we determined if 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 the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of glucocorticoid receptor (GR) or peroxisome proliferator-activated receptor γ (PPARγ). 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 assay indicated that tamoxifen and 4-hydroxytamoxifen activated the negative glucocorticoid regulatory element (nGRE) but inhibited the PPARγ regulatory element (PPRE) in the FABP4 gene. In vivo, administration of tamoxifen to apoE deficient (apoE-/-) mice on 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, our study shows that tamoxifen inhibited FABP...
Source: BJ Signal - Category: Biochemistry Authors: Tags: BJ Metabolism Source Type: research