Transcriptional and posttranscriptional repression of histone deacetylases by docosahexaenoic acid in macrophages

Abstract

Histone deacetylation is one of the posttranslational modifications of histones by which eukaryotic cells alter gene transcription. Although fatty acids are the best known macronutrients that modulate gene expression in inflammatory pathways, it is unclear whether common fatty acids in diets can regulate the expression of histone deacetylases (HDACs) in macrophages. We determined the effects of fatty acids, including palmitic acid (PA), oleic acid (OA), linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the expression of HDAC isoforms in RAW 264.7 macrophages, mouse bone marrow-derived macrophages (BMDM) and human THP-1 cells. In RAW 264.7 macrophages, OA significantly increased mRNA levels of Hdac1, 2 and 3, and EPA induced Hdac2 expression compared with control. Marked repression of Hdac9 mRNA levels by EPA and DHA, with DHA being more potent, was observed in RAW 264.7 macrophages and BMDM. DHA also decreased HDAC3, 4 and 9 protein levels. EPA and DHA facilitated the proteasomal degradation of HDAC3 and 4 protein, while the transcriptional repression of HDAC9 by DHA may be mediated by the repression of myocyte enhancer factor 2 or by the activation of retinoid X receptor. Functionally, inhibition of HDAC activity or knockdown of Hdac9 in macrophages reduced lipopolysaccharide-induced inflammatory gene expression. Our results demonstrate that DHA represses the expression of HDAC3, 4 and 9 at the transcriptional or posttranscriptional levels in murine macrophages. This suggests that the anti-inflammatory effect of DHA may be mediated by the reduction of HDACs.