Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Buczynski, Matthew W.; Dumlao, Darren S.; Dennis, Edward A.

doi:10.1194/jlr.r900004-jlr200

Cited by 467 publications

(486 citation statements)

References 250 publications

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“…We have previously observed a preferential increase in 5-LOX vs. COX-1 AA metabolites when RAW cells were primed with TLR4 stimulation and subsequent P2X 7 stimulation that was independent of protein synthesis (17). In this same study, AA was synergistically increased along with AA 5-LOX metabolites but not COX-1 metabolites.…”

Section: Discussionsupporting

confidence: 63%

“…S2), and found that cPLA 2 hydrolysis of DHA was dependent on P2X 7 , but not TLR4 stimulation. Interestingly, TLR4 priming and subsequent stimulation of P2X 7 led to synergistic release of DHA, which we have previously demonstrated with AA (17).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, when murine resident peritoneal macrophages (RPM) were supplemented with 10 μM EPA, ∼75% of the increased EPA in phospholipids was in the elongated form, DPA. Ultimately, DPA was the only PUFA released at a comparable level to AA for competition after P2X 7 stimulation, and COX AA eicosanoids were reduced after P2X 7 and TLR4 stimulation similar to RAW cells ( Fig. 3 and Fig.…”

Section: Effects Of 22-carbon Fatty Acid Supplementation On Eicosanoidmentioning

confidence: 93%

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

Norris

Dennis²

2012

Proc. Natl. Acad. Sci. U.S.A.

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161

129

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Dietary fish oil omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti‐inflammatory effects through unresolved mechanisms. EPA and DHA may reduce arachidonic acid (AA) metabolism and pro‐inflammatory effects by competition and inhibition at multiple levels. Here, we report the effects of AA, EPA, and DHA supplementation on membrane incorporation, phospholipase A2 release, and eicosanoid production in RAW264.7 macrophages. Each PUFA supplemented increased by similar amounts in membrane phospholipids, while half of the increased AA and EPA were elongated to adrenic acid (AdA) and docosapentaenoic acid (DPA), respectively; and were subsequently released by PLA2 at levels comparable to AA. TLR‐4 stimulated COX‐2 AA production did not increase with AA supplementation and was inhibited by 20% and 50% after EPA and DHA supplementation, respectively. ATP stimulated COX‐1 AA production was inhibited to a greater extent by EPA and DHA; 5‐LOX AA metabolites increased 2‐fold with EPA and DHA supplementation, and 5‐LOX metabolized EPA and DHA to a greater extent than COX‐1/COX‐2. Altogether, AA, EPA and DHA supplementation decreased TLR‐4 stimulated AA COX‐2 prostanoid metabolism; increased the purinergic stimulated AA 5‐LOX/COX‐1 ratio; and significantly increased elongated PUFA levels that may be converted to novel mediators.

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Effects Of 22-carbon Fatty Acid Supplementation On Eicosanoidmentioning

confidence: 93%

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

Norris

Dennis²

2012

Proc. Natl. Acad. Sci. U.S.A.

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161

129

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“…Most saturated and monounsaturated VLCFAs are sphingolipid components and so play important roles in skin barrier formation and neural functions (2,3). PUFAs of the n-6 series (e.g., C20:4) are involved in the promotion of inflammation as precursors of eicosanoids (4). PUFAs of the n-3 series (e.g., C20:5 and C22:6) are effective in the prevention of arteriosclerosis, heart failure, and age-related macular degeneration by virtue of their roles in reducing plasma triglycerides, lowering blood pressure, and suppressing inflammation (5).…”

mentioning

confidence: 99%

ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis

Ohno

Suto

Yamanaka

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

304

354

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Very long-chain fatty acids (VLCFAs) exert a variety of cellular functions and are associated with numerous diseases. However, the precise pathway behind their elongation has remained elusive. Moreover, few regulatory mechanisms for VLCFAs synthesis have been identified. Elongases catalyze the first of four steps in the VLCFA elongation cycle; mammals have seven elongases (ELO-VL1-7). In the present study, we determined the precise substrate specificities of all the ELOVLs by in vitro analyses. Particularly notable was the high activity exhibited by ELOVL1 toward saturated and monounsaturated C20-and C22-CoAs, and that it was essential for the production of C24 sphingolipids, which are unique in their capacity to interdigitate within the membrane as a result of their long chain length. We further established that ELOVL1 activity is regulated with the ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. This regulation may ensure that the production of C24-CoA by elongation is coordinated with its utilization. Finally, knockdown of ELOVL1 caused a reduction in the activity of the Src kinase LYN, confirming that C24-sphingolipids are particularly important in membrane microdomain function.acyl-CoA | lipid metabolism | monounsaturated fatty acid | polyunsaturated fatty acid | saturated fatty acid

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“…11). So far, this focus has led to a robust and comprehensive approach to the lipidomics analysis of hundreds of fatty acids including their numerous metabolites arising from an array of cyclooxygenases, lipoxygenases, cytochrome P450s, and non-enzymatic oxidation reactions (164), such as the production of dihomoprostaglandins in stimulated macrophages resulting from the elongation of arachidonic acid to adrenic acid (165). We also used lipidomics to analyze very long chain fatty acids that are particularly abundant in the phospholipids of retinal membranes where they are critical for function (166) and demonstrated the essential role of ELOVL-4 in the synthesis of these fatty acids.…”

Section: Lipidomics Of Fatty Acids and Eicosanoidsmentioning

confidence: 99%

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Dennis

2016

Journal of Biological Chemistry

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In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A 2 (PLA 2 ) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral informationcontaining signaling molecules; for example, PLA 2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

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Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Cited by 467 publications

References 250 publications

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

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

ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

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