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Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling.

ABSTRACT: Dietary fish oil containing ?3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti-inflammatory effects through unresolved mechanisms that may involve competition and inhibition at multiple levels. Here, we report the effects of arachidonic acid (AA), EPA, and DHA supplementation on membrane incorporation, phospholipase A(2) catalyzed release, and eicosanoid production in RAW264.7 macrophages. Using a targeted lipidomics approach, we observed that Toll-like receptor 4 and purinergic receptor activation of supplemented cells leads to the release of 22-carbon fatty acids that potently inhibit cyclooxygenase pathways. This inhibition was able to shunt metabolism of AA to lipoxygenase pathways, augmenting leukotriene and other lipoxygenase mediator synthesis. In resident peritoneal macrophages, docosapentaenoic acid (DPA) was responsible for cyclooxygenase inhibition after EPA supplementation, offering fresh insights into how EPA exerts anti-inflammatory effects indirectly through elongation to 22-carbon DPA.

SUBMITTER: Norris PC

PROVIDER: S-EPMC3365225 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling.

Norris Paul C PC Dennis Edward A EA

Proceedings of the National Academy of Sciences of the United States of America 20120514 22

Dietary fish oil containing ω3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti-inflammatory effects through unresolved mechanisms that may involve competition and inhibition at multiple levels. Here, we report the effects of arachidonic acid (AA), EPA, and DHA supplementation on membrane incorporation, phospholipase A(2) catalyzed release, and eicosanoid production in RAW264.7 macrophages. Using a targeted lipidomics approach, we observed ...[more]

PMID: 22586114

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Project description:BackgroundAlthough omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.Methods and resultsAmong 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.ConclusionsHigh circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

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Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling.

Publications

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling.

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