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Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism

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Abstract

Linoleic acid (LA, 18:2n-6) is a precursor to arachidonic acid (AA, 20:4n-6), which can be converted by brain lipoxygenase and cyclooxygenase (COX) enzymes into various lipid mediators involved in the regulation of brain immunity. Brain AA metabolism is activated in rodents by the bacterial endotoxin, lipopolysaccharide (LPS). This study tested the hypothesis that dietary LA lowering, which limits plasma supply of AA to the brain, reduces LPS-induced upregulation in brain AA metabolism. Male Fischer CDF344 rats fed an adequate LA (5.2 % energy (en)) or low LA (0.4 % en) diet for 15 weeks were infused with LPS (250 ng/h) or vehicle into the fourth ventricle for 2 days using a mini-osmotic pump. The incorporation rate of intravenously infused unesterified 14C-AA into brain lipids, eicosanoids, and activities of phospholipase A2 and COX-1 and 2 enzymes were measured. Dietary LA lowering reduced the LPS-induced increase in prostaglandin E2 concentration and COX-2 activity (P < 0.05 by two-way ANOVA) without altering phospholipase activity. The 14C-AA incorporation rate into brain lipids was decreased by dietary LA lowering (P < 0.05 by two-way ANOVA). The present findings suggest that dietary LA lowering reduced LPS-induced increase in brain markers of AA metabolism. The clinical utility of LA lowering in brain disorders should be explored in future studies.

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Abbreviations

α-LNA:

Alpha–linolenic acid

AA:

Arachidonic acid

ACSF:

Artificial cerebrospinal fluid

ANOVA:

Analysis of variance

cPLA2 :

Calcium-dependent phospholipase A2

COX:

Cyclooxygenase

DHA:

Docosahexaenoic acid

DPA:

Docosapentaenoic acid

en:

Energy

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunoassay

EPA:

Eicosapentaenoic acid

FAMEs:

Fatty acid methyl esters

GC:

Gas-chromatography

HETE:

Hydroxy-eicosatetraenoic acid

i.c.v.:

Intracerebroventricular

iPLA2 :

Calcium-independent phospholipase A2

LA:

Linoleic acid

PG:

Prostaglandin

PUFA:

Polyunsaturated fatty acid

sPLA2 :

Secretory phospholipase A2

TX:

Thromboxane

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Acknowledgments

The authors thank Vasken Keleshian for his assistance in feeding the rats, and Dr. Jagadeesh Rao for proposing to study the role of omega-6 fatty acids on neuroinflammation. This study was supported in part by a grant from the Office of Dietary Supplements (OD-Y2-OD-2005-01) and the National Institute on Aging Intramural Research Program.

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Authors and Affiliations

  1. Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, One Shields Avenue, Davis, CA, 95616, USA

    Ameer Y. Taha

  2. Brain Physiology and Metabolism Section, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    Helene C. Blanchard, Yewon Cheon, Epolia Ramadan, Mei Chen, Lisa Chang & Stanley I. Rapoport

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  1. Ameer Y. Taha
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ESM 1

Supplementary Fig. 1: Scatter plot of brain eicosanoid and docosanoid concentrations in adequate and low LA rats treated with i.c.v. ACSF or LPS for 2 days. There were no significant differences by two-way ANOVA. Supplementary Table 1: Number of subjects per group for each experiment and documentation of animal or sample loss. Supplementary Table 2: Log-transformed brain eicosanoid and docosanoid concentrations following 2-day ACSF or LPS infusion to low or adequate LA rats. (DOCX 112 kb)

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Taha, A.Y., Blanchard, H.C., Cheon, Y. et al. Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism. Mol Neurobiol 54, 4303–4315 (2017). https://doi.org/10.1007/s12035-016-9968-1

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