Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1862, Issue 5, Pages 552-560Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2017.02.010
Keywords
Autophagy; Inflammation; Microglia; NF-kappa B; SIRT1; omega-3 PUFAs
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [16H07498, 16K09276, 16K08959, 15K08634]
- Japan Agency for Medical Research and Development
- Takeda Science Foundation
- Japan Research Foundation for Clinical Pharmacology
- Kao Research Council for the Study of Healthcare Science
- 5th Annual Research Award Grant of Japanese Society of Anti-Aging Medicine
- Smoking Research Foundation
- Nestle Nutrition Council, Japan
- National Hospital Organization [H26-NHO-02]
- Grants-in-Aid for Scientific Research [16K08959, 16K09276, 16H07498, 15K08634] Funding Source: KAKEN
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Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA + DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-alpha and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA + DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA + DHA also inhibited phosphorylation of the stress-associated transcription factor NF-KB subunit p65 at Ser536, which is known to enhance NF-KB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA + DHA increased the LO-II/LO-I ratio, an indicator of autophagy. Suppression of TNF-alpha and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-alpha suppression but not IL-6 suppression. Accordingly, these omega-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-KB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and-unrelated pathways. (C) 2017 Elsevier B.V. All rights reserved.
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