Lipidomics: New signals to stop and protect

Lipidomics Gateway (28 September 2011) [doi:10.1038/lipidmaps.2011.27]

A lipidomics study in tandem with a functional screen has identified novel potent bioactive signals from the DHEA metabolome that inhibit leukocyte chemotaxis and confer anti-inflammatory and organ-protective properties.

Docosahexaenoic acid (DHA) has received much attention for its ability to reduce inflammation and the extent of tissue damage, particularly in the brain. These beneficial effects have so far largely been attributed to D series resolvins, such as 7,17-dihydroxydocosahexaenoic acid (7,17-diHDHA; resolvin D5), and 10,17-diHDHA, better known as neuroprotectin D1, that are biosynthesized from DHA. However, in light of recent findings by Yang et al., credit should also be given to novel bioactive products from docosahexaenoyl ethanolamide (DHEA), the ethanolamine amide of DHA.

Yang et al. began their functional metabolomics study by subjecting mouse brain extracts to liquid chromatography-tandem mass-spectrometry (LC-UV-MS-MS). In parallel, the DHEA metabolites were introduced into microfluidic chambers to assess their potential influence on the chemotaxis of human polymorphonuclear leukocytes (PMNs). The brain metabolite mixture markedly reduced interleukin-8-induced PMN chemotaxis, indicating the presence of at least one bioactive product among the metabolites.

One of the metabolites identified from the brain was 17-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoylethanolamide (17-HDHEA). Further analysis of the metabolic fates of 17-HDHEA using LC-UV-MS-MS-based lipidomics in mouse brain incubated with DHEA, human haemoglobin incubated with 17-hydroperoxy-DHEA (17-HpDHEA) or PMNs incubated with DHEA or 17-HpDHEA led to the identification of 4,17-diHDHEA, 7,17-diHDHEA, 10,17-diHDHEA and 15-hydroxy-16(17)-epoxydocosa-4Z,7Z,10Z,3Z,19Z-pentaenoylethanolamide (15-HEDPEA). When Yang et al. screened each of these products, 15-HEDPEA effectively induced morphology changes and inhibited PMN migration in the IL-8 gradient at 10 nM; only at higher concentrations (10 μM) did the other deoxygenated DHEA products affect chemotaxis.

To investigate how these DHEA-derived products mediated their effects, the authors tested their ability to activate cannabinoid receptors, similar to the related anandamide N-acyl-arachidonoyl-ethanolamide (AEA). Both 10,17-diHDHEA or 15-HEDPEA bound to and activated cannabinoid type 2 receptors with nanomolar affinity; they also activated type 1 receptors, although this required much higher concentrations.

Given the generation of 10,17-diHDHEA and 15-HEDPEA by PMNs, and the involvement of platelet–leukocyte interactions in haemostasis, thrombosis and inflammation, the authors investigated the functions of these two DHEA-derived products on platelet–leukocyte aggregate formation in human whole blood. Both reduced the formation of platelet–monocyte aggregates induced by platelet-activating factor (PAF) in human whole blood by ~30%, and 10,17-diHDHEA also potently inhibited PAF-stimulated platelet–PMN aggregate formation. Finally, in light of the ability of 15-HEDPEA to inhibit PMN chemotaxis and platelet–monocyte aggregate formation, its potential role in preventing second organ reperfusion injuries following ischaemia was studied. After hind limb occlusion in mice, 15-HEDPEA inhibited PMN infiltration into the lung by ~50%, thereby decreasing associated lung injury.

Yang et al. have therefore combined lipidomics with functional screening to identify potent novel bioactive molecules generated by DHEA oxidative metabolism that reduce inflammation and organ injury. This DHEA metabolome might well contribute considerably to the established anti-inflammatory and tissue-injury-reducing effects currently attributed to DHA, and highlights a potential therapeutic role for these novel molecules.

Katrin Legg

References:

ORIGINAL RESEARCH PAPER

1. Yang, R. et al. Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals.
   J. Biol. Chem. 286, 31532-31541 (2011). doi:10.1074/jbc.M111.237990