Identifying and understanding anti-inflammatory effects of 18-carbon fatty acids from sustainable plant sources

Abstract

Epidemiological studies and randomised control trials demonstrate an association between high consumption of very-long chain (VLC) n-3 polyunsaturated fatty acids (PUFAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and long-term health benefits. One of the key actions of EPA and DHA is to reduce inflammation. The principal source of EPA and DHA is oily fish. Current stocks of fatty fish are likely not sufficient to meet the needs of humans for VLC n-3 PUFAs. Alphalinolenic acid (ALA), stearidonic acid (SDA), gamma-linolenic acid (GLA) and pinolenic acid (PIN) may provide sustainable land-based sources of FAs to promote human health, but their functionality has been underexplored, including in relation to inflammation. Dysfunction of vascular endothelial cells (ECs) plays a vital role in the development of atherosclerosis. Incorporation of DHA, and to a lesser extent EPA, into EC lipids has been shown to decrease cytokine-induced expression of adhesion molecules and secretion of inflammatory mediators.

The research described in this thesis explores the effects of ALA, SDA, GLA and PIN, in comparison with EPA and DHA, as well as different ratios of linoleic acid (LA) to ALA on inflammatory responses of a cultured EC line (EA.hy926 cells).

All FAs examined were incorporated into the ECs in a dose-dependent manner, with several elongation products being synthesised; of these the elongation product of PIN, eicosatrienoic acid (ETrA), was successfully identified using GC-MS. Of the two marine-derived FAs DHA had the most potent anti-inflammatory effect in EA.hy926 cells. Both EPA and DHA decreased production of all inflammatory mediators studied, cell surface expression of ICAM-1, and intracellular inflammatory proteins, and significantly modulated the expression of various inflammatory genes. DHA decreased adhesion of THP-1 monocytes to EA.hy926 cells under static conditions. Of the plant-derived FAs, GLA and PIN caused the greatest reduction in inflammatory mediator production. Gene expression was altered by both GLA and SDA; additionally, SDA reduced cell surface expression of ICAM-1. Lastly, all plant-derived FAs decreased THP-1 adhesion to EA.hy926 cells. FA effects were concentration dependent. No plant-derived FA was as potent as DHA. Silencing of the elongase 5 gene significantly inhibited the production of DGLA and ETrA in EA.hy926 cells pre-treated with GLA and PIN. Furthermore, most of the anti-inflammatory effects of GLA and PIN were abolished by silencing elongase 5 suggesting that GLA and PIN act via their elongation products. ALA and ratios of LA to ALA containing higher concentrations of ALA were anti-inflammatory in EA.hy926 cells.

These findings confirm anti-inflammatory effects of EPA and DHA in ECs. New anti-inflammatory actions of plant-derived FAs are identified, although these FAs are less potent than DHA. Nevertheless, these findings suggest that plant-derived FAs, especially GLA and PIN have potential as sustainable anti-inflammatory alternatives to EPA and DHA. Further research on these FAs is warranted.

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Identifiers

ORCID for Philip Calder: orcid.org/0000-0002-6038-710X

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