The regulation of inflammation-related genes after palmitic acid and DHA treatments is not mediated by DNA methylation
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Fatty acids (FAs) are known to participate in body inflammatory responses. In particular, saturated FAs such as palmitic acid (PA) induce inflammatory signals in macrophages, whereas polyunsaturated FAs, including docosahexaenoic acid (DHA), have been related to anti-inflammatory effects. Several studies have suggested a role of fatty acids on DNA methylation, epigenetically regulating gene expression in inflammation processes. Therefore, this study investigated the effect of PA and DHA on the inflammation-related genes on human macrophages. In addition, a second aim was to study the epigenetic mechanism underlying the effect of FAs on the inflammatory response. For these purposes, human acute monocytic leukaemia cells (THP-1) were differentiated into macrophages with 12-O-tetradecanoylphorbol-13-acetate (TPA), followed by an incubation with PA or DHA. At the end of the experiment, mRNA expression, protein secretion, and CpG methylation of the following inflammatory genes were analysed: interleukin 1 beta (IL1B), tumour necrosis factor (TNF), plasminogen activator inhibitor-1 (SERPINE1) and interleukin 18 (IL18). The results showed that the treatment with PA increased IL-18 and TNF-α production. Contrariwise, the supplementation with DHA reduced IL-18, TNF-α and PAI-1 secretion by macrophages. However, the incubation with these fatty acids did not apparently modify the DNA methylation status of the investigated genes in the screened CpG sites. This research reveals that PA induces important pro-inflammatory markers in human macrophages, whereas DHA decreases the inflammatory response. Apparently, DNA methylation is not directly involved in the fatty acid-mediated regulation of the expression of these inflammation-related genes.
KeywordsEpigenetics Cytokines Macrophages PUFA Saturated fatty acids
We thank the technical assistance of Enrique Buso (UCIM, University of Valencia) for the MassARRAY® measurements.
This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness under grant AGL2013-45554-R; the Spanish Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn); and the Brazilian Ministry of Education, Culture and Sport under grant BES-2014-068409.
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Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
This article does not contain any individual participants.
- 4.Arpón A, Milagro FI, Razquin C, Corella D, Estruch R, Fitó M, Marti A, Martínez-González M, Ros E, Salas-Salvadó J, Riezu-Boj JI, Martínez J (2018) Impact of consuming extra-virgin olive oil or nuts within a mediterranean diet on DNA methylation in peripheral white blood cells within the PREDIMED-Navarra randomized controlled trial: a role for dietary lipids. Nutrients 10:15. https://doi.org/10.3390/nu10010015 CrossRefGoogle Scholar
- 8.Cho Y, Turner ND, Davidson LA, Chapkin RS, Carroll RJ, Lupton JR (2014) Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med 239:302–310. https://doi.org/10.1177/1535370213514927 CrossRefGoogle Scholar
- 10.Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, Cantor CR, Field JK, van den Boom D (2005) Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci 102:15785–15790. https://doi.org/10.1073/pnas.0507816102 CrossRefPubMedGoogle Scholar
- 11.Flores-Sierra J, Arredondo-Guerrero M, Cervantes-Paz B, Rodríguez-Ríos D, Alvarado-Caudillo Y, Nielsen FC, Wrobel K, Wrobel K, Zaina S, Lund G (2016) The trans fatty acid elaidate affects the global DNA methylation profile of cultured cells and in vivo. Lipids Health Dis 15:75. https://doi.org/10.1186/s12944-016-0243-2 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Fogel O, Richard-Miceli C, Tost J (2017) Epigenetic changes in chronic inflammatory diseases. In: Advances in protein chemistry and structural biology. Academic Press, pp 139–189Google Scholar
- 14.García-Escobar E, Monastero R, García-Serrano S, Gómez-Zumaquero JM, Lago-Sampedro A, Rubio-Martín E, Colomo N, Rodríguez-Pacheco F, Soriguer F, Rojo-Martínez G (2017) Dietary fatty acids modulate adipocyte TNFa production via regulation of its DNA promoter methylation levels. J Nutr Biochem 47:106–112. https://doi.org/10.1016/j.jnutbio.2017.05.006 CrossRefPubMedGoogle Scholar
- 15.González-Muniesa P, De Oliveira C, Pérez De Heredia F et al (2011) Fatty acids and hypoxia stimulate the expression and secretion of the adipokine ANGPTL4 (angiopoietin-like protein 4/ fasting-induced adipose factor) by human adipocytes. J Nutrigenet Nutrigenomics 4:146–153. https://doi.org/10.1159/000327774 CrossRefPubMedGoogle Scholar
- 17.He Z, Zhang R, Jiang F, Zhang H, Zhao A, Xu B, Jin L, Wang T, Jia W, Jia W, Hu C (2018) FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression. Clin Epigenetics 10:113. https://doi.org/10.1186/s13148-018-0545-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, Landerholm RW, Crouthamel M, Gozal D, Hwang S, Singh PK, Becker L (2014) Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20:614–625. https://doi.org/10.1016/j.cmet.2014.08.010 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Ma Y, Smith CE, Lai C-Q, Irvin MR, Parnell LD, Lee YC, Pham LD, Aslibekyan S, Claas SA, Tsai MY, Borecki IB, Kabagambe EK, Ordovás JM, Absher DM, Arnett DK (2016) The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter. Mol Nutr Food Res 60:410–419. https://doi.org/10.1002/mnfr.201500436 CrossRefPubMedGoogle Scholar
- 31.Mullen A, Loscher CE, Roche HM (2010) Anti-inflammatory effects of EPA and DHA are dependent upon time and dose-response elements associated with LPS stimulation in THP-1-derived macrophages. J Nutr Biochem 21:444–450. https://doi.org/10.1016/j.jnutbio.2009.02.008 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Nicoletti CF, Nonino CB, de Oliveira BAP, Pinhel MAS, Mansego ML, Milagro FI, Zulet MA, Martinez JA (2016) DNA methylation and Hydroxymethylation levels in relation to two weight loss strategies: energy-restricted diet or bariatric surgery. Obes Surg 26:603–611. https://doi.org/10.1007/s11695-015-1802-8 CrossRefPubMedGoogle Scholar
- 33.Oliver E, McGillicuddy FC, Harford KA et al (2012) Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA. J Nutr Biochem 23:1192–1200. https://doi.org/10.1016/j.jnutbio.2011.06.014 CrossRefPubMedGoogle Scholar
- 35.Perfilyev A, Dahlman I, Gillberg L, Rosqvist F, Iggman D, Volkov P, Nilsson E, Risérus U, Ling C (2017) Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial. Am J Clin Nutr 105:991–1000. https://doi.org/10.3945/ajcn.116.143164 CrossRefPubMedGoogle Scholar
- 36.Pot GK, Brouwer IA, Enneman A, Rijkers GT, Kampman E, Geelen A (2009) No effect of fish oil supplementation on serum inflammatory markers and their interrelationships: a randomized controlled trial in healthy, middle-aged individuals. Eur J Clin Nutr 63:1353–1359. https://doi.org/10.1038/ejcn.2009.63 CrossRefPubMedGoogle Scholar
- 48.Silva Figueiredo P, Carla Inada A, Marcelino G, Maiara Lopes Cardozo C, de Cássia Freitas K, de Cássia Avellaneda Guimarães R, Pereira de Castro A, Aragão do Nascimento V, Aiko Hiane P (2017) Fatty acids consumption: the role metabolic aspects involved in obesity and its associated disorders. Nutrients 9:1158. https://doi.org/10.3390/nu9101158 CrossRefPubMedCentralGoogle Scholar
- 49.Silva-Martínez GA, Rodríguez-Ríos D, Alvarado-Caudillo Y, Vaquero A, Esteller M, Carmona FJ, Moran S, Nielsen FC, Wickström-Lindholm M, Wrobel K, Wrobel K, Barbosa-Sabanero G, Zaina S, Lund G (2016) Arachidonic and oleic acid exert distinct effects on the DNA methylome. Epigenetics 11:321–334. https://doi.org/10.1080/15592294.2016.1161873 CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Snodgrass RG, Huang S, Namgaladze D, Jandali O, Shao T, Sama S, Brüne B, Hwang DH (2016) Docosahexaenoic acid and palmitic acid reciprocally modulate monocyte activation in part through endoplasmic reticulum stress. J Nutr Biochem 32:39–45. https://doi.org/10.1016/j.jnutbio.2016.01.010 CrossRefPubMedGoogle Scholar
- 52.Tsai EY, Falvo JV, Tsytsykova AV, Barczak AK, Reimold AM, Glimcher LH, Fenton MJ, Gordon DC, Dunn IF, Goldfeld AE (2000) A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo. Mol Cell Biol 20:6084–6094CrossRefPubMedPubMedCentralGoogle Scholar