Transcriptional and posttranscriptional repression of histone deacetylases by docosahexaenoic acid in macrophages |
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| Affiliation: | 1. Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA;2. Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea;1. Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA;2. Department of Pharmacology Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Sciences, University of Barcelona;3. IBUB (Institute of Biomedicine, University of Barcelona);4. CIBERobn (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición);1. Department of Biochemistry, Memorial University of Newfoundland, St. John''s, NL, Canada A1B 3X9;2. Department of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John''s, NL, Canada A1B 3V6;3. Diabetes & Nutritional Sciences Division, King''s College, London, United Kingdom SE1 9NH;1. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia;2. Service de Pneumologie, CHU de Toulouse Hôpital Larrey, Toulouse, France;3. Department of Surgery, John Hunter Hospital, New Lambton Heights, New South Wales, Australia;4. Sea Change Weight Loss Clinic, Merewether, New South Wales, Australia;1. Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá/PR, Brazil;2. Institute of Health Sciences, Federal University of Mato Grosso, Sinop, MT, Brazil;3. Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro/RJ, Brazil |
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| 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. |
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