Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts
| Autor: | Florian Gruber, Marie-Sophie Narzt, Susanne Karner, Erwin Tschachler, Cayo Mecking Ornelas, Ionela Mariana Nagelreiter, Valery N. Bochkov, Maria Gschwandtner |
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| Rok vydání: | 2015 |
| Předmět: |
Cell signaling
Docosahexaenoic Acids NF-E2-Related Factor 2 Ultraviolet Rays Blotting Western Phospholipid Biology medicine.disease_cause Biochemistry Immunoenzyme Techniques Mice chemistry.chemical_compound Lipid oxidation Tandem Mass Spectrometry Physiology (medical) medicine Animals Humans Fibroblast Chromatography High Pressure Liquid Skin Inflammation chemistry.chemical_classification Reverse Transcriptase Polymerase Chain Reaction Fibroblasts medicine.anatomical_structure chemistry Docosahexaenoic acid lipids (amino acids peptides and proteins) Tumor necrosis factor alpha Lipid Peroxidation Oxidative stress Polyunsaturated fatty acid |
| Zdroj: | Free Radical Biology and Medicine. 88:439-451 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2015.05.006 |
| Popis: | Fish oil rich in docosahexaenoic acid (DHA) has beneficial effects on human health. Omega-3 polyunsaturated fatty acids are precursors of eicosanoids and docosanoids, signaling molecules that control inflammation and immunity, and their dietary uptake improves a range of disorders including cardiovascular diseases, ulcerative colitis, rheumatoid arthritis, and psoriasis. The unsaturated nature of these fatty acids, however, makes them prone to oxidation, especially when they are incorporated into (membrane) phospholipids. The skin is an organ strongly exposed to oxidative stress, mainly due to solar ultraviolet radiation. Thus, increased levels of PUFA in combination with oxidative stress could cause increased local generation of oxidized lipids, whose action spectrum reaches from signaling molecules to reactive carbonyl compounds that can crosslink biomolecules. Here, we investigated whether PUFA supplements to fibroblasts are incorporated into membrane phospholipids and whether an increase of PUFA within phospholipids affects the responses of the cells to UV exposure. The redox-sensitive transcription factor Nrf2 is the major regulator of the fibroblast stress response to ultraviolet radiation or exposure to oxidized lipids. Here we addressed how Nrf2 signaling would be affected in PUFA-supplemented human dermal fibroblasts and mouse dermal fibroblasts from Nrf2-deficient and wild type mice. We found, using HPLC-tandem MS, that DHA supplements to culture media of human and murine fibroblasts were readily incorporated into phospholipids and that subsequent irradiation of the supplemented cells with UVA resulted in an increase in 1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphorylcholine and Oxo-DHA esterified to phospholipid, both of which are Nrf2 agonists. Also, induction of Nrf2 target genes was enhanced in the DHA-supplemented fibroblasts after UVA irradiation. In Nrf2-deficient murine fibroblasts, the expression of the target genes was, as expected, decreased, but surprisingly, expression of TNFα and MMP13 was strongly induced in DHA-supplemented, UVA-irradiated cells. Also, Nrf2-deficient cells had increased levels of oxidized phospholipids relative to the unoxidized precursors after UVA irradiation. Our data suggest that under ultraviolet stress a functioning Nrf2 system is required to prevent DHA-induced inflammation and matrix degradation in dermal fibroblasts. |
| Databáze: | OpenAIRE |
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