Bioactive metabolites of docosahexaenoic acid

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Jan 11, 2017 - Maresin 1 (7R,14S-diHDHA, conjugated triene E,E,Z) displays potent anti-inflammatory, pro-resolving, analgesic and pro-healing actions [28 ...
Biochimie 136 (2017) 12e20

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Review

Bioactive metabolites of docosahexaenoic acid Ondrej Kuda Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic

a r t i c l e i n f o

a b s t r a c t

Article history: Received 7 October 2016 Received in revised form 2 January 2017 Accepted 8 January 2017 Available online 11 January 2017

Docosahexaenoic acid (DHA) is an essential fatty acid that is recognized as a beneficial dietary constituent and as a source of the anti-inflammatory specialized proresolving mediators (SPM): resolvins, protectins and maresins. Apart from SPMs, other metabolites of DHA also exert potent biological effects. This article summarizes current knowledge on the metabolic pathways involved in generation of DHA metabolites. Over 70 biologically active metabolites have been described, but are often discussed separately within specific research areas. This review follows DHA metabolism and attempts to integrate the diverse DHA metabolites emphasizing those with identified biological effects. DHA metabolites could be divided into DHA-derived SPMs, DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids. These bioactive metabolites have pleiotropic effects that include augmenting energy expenditure, stimulating lipid catabolism, modulating the immune response, helping to resolve inflammation, and promoting wound healing and tissue regeneration. As a result they have been shown to exert many beneficial actions: neuroprotection, anti-hypertension, anti-hyperalgesia, anti-arrhythmia, anti-tumorigenesis etc. Given the chemical structure of DHA, the number and geometry of double bonds, and the panel of enzymes metabolizing DHA, it is also likely that novel bioactive derivatives will be identified in the future. © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Keywords: DHA Specialized proresolving mediators FAHFA DHEA N-acyl amides Omega-3 PUFA

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Enzymes metabolizing DHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Oxygenated metabolites of DHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.1. Maresins - resolution of inflammation, wound healing, analgesic actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.2. Protectins - resolution of inflammation, neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3. Resolvins - resolution of inflammation and wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.4. Electrophilic oxo-derivatives (EFOX) of DHA e anti-inflammatory, anti-proliferative effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.5. Epoxides e anti-hypertensive, analgesic actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.6. Neuroprostanes e cardioprotection, wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Conjugates of DHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.1. Ethanolamines and glycerol esters e neural development, immunomodulation, metabolic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.2. Branched fatty acid esters of hydroxy fatty acids (FAHFA) e immunomodulation, resolution of inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.3. N-acyl amides - metabolic regulation, neuroprotection, neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

E-mail address: [email protected]. http://dx.doi.org/10.1016/j.biochi.2017.01.002 0300-9084/© 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

O. Kuda / Biochimie 136 (2017) 12e20

1. Introduction Naturally occurring long-chain omega-3 polyunsaturated fatty acids (omega-3), namely eicosapentaenoic acid (EPA; 20:5 u-3) and docosahexaenoic acid (DHA; 22:6 u-3), have many beneficial metabolic effects, including prevention of cardiovascular diseases [1], amelioration of non-alcoholic fatty liver disease [2], or lowering hypertriacylglycerolemia [3]. They exert anti-inflammatory and hypolipidemic effects (reviewed in Ref. [4]), while increasing catabolism of lipids via a PPARa-mediated mechanism [4e6]. Although negative effects of omega-3 PUFA on prostate cancer risk [7] and prevention of cardiovascular diseases [8] were published these findings were later revised [9e11]. The discrepancies probably reflect multiple variables that could complicate the outcome of these studies (reviewed in Ref. [4]) and suggest that omega-3 dose and context (medication, disease) have to be considered. Patients who could potentially benefit from omega-3 supplementation are often premedicated with over-the-counter nonsteroidal antiinflammatory drugs, pain relievers, statins or other drugs which could interact with lipid metabolism and eicosanoid/docosanoid production and neutralize the potential of omega-3. In addition there is information suggesting that genetic variants can explain some of the individual variability in therapeutic potential of omega-3 supplementation [12,13]. Despite the occasionally divergent findings, omega-3 are generally considered as food supplements with positive properties. The beneficial effects of DHA are mediated by the fatty acid itself (PPARa ligand [14,15]) as well as by its bioactive metabolites e the specialized proresolving mediators (SPM) and other DHA derivatives. Although DHA triggers signaling through the Free fatty acid receptor 4 (FFAR4, also known as G protein-coupled receptor 120; GPR120) [16e18], recent studies have shown that FFAR4 is not required for the anti-inflammatory and insulin sensitizing effects of omega-3 [19e21] supporting existence of additional DHA receptors. The DHA metabolites have a wide range of actions acting simultaneously at different levels and sites. They activate various cell surface receptors (GPR32, GPR110, N-formyl peptide receptor 2; cannabinoid receptor 1 & 2; transient receptor potential channels; etc.) [22e25], and they also act as ligands to nuclear receptors PPARa/g [26,27]. 2. Enzymes metabolizing DHA Dominant enzymes in DHA metabolism are the 5-, 12-, and 15lipoxygenases (LOX) that form DHA hydroperoxides (HpDHA), which are further metabolized by hydrolases, including soluble epoxide hydrolase (sEH), glutathione S-transferase (GST) and several members of the cytochrome P450 superfamily (epoxydases, u-hydrolases) [22,28]. Cyclooxygenase (COX; prostaglandinendoperoxide synthase) 2 also metabolizes DHA, especially when its active site is acetylated by aspirin [29]. Degradation of active metabolites is carried out via oxidation (15-hydroxyprostaglandin dehydrogenase, 15PGDH), conjugation with glutathione (GSH) or hydrolysis by fatty acid amide hydrolase (FAAH) or sEH [30e32]. Only little is known about the synthesis and degradation of N-acylamides [33].

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namely protectins, resolvins and maresins, according to their structures and biological effects [22,28]. For further details on SPMs (stereochemistry, organic synthesis, etc), readers are directed to recent reviews [28,35]. See Figs. 1e3 and Supplemental Fig. 1 for a schematic overview of the related pathways. 3.1. Maresins - resolution of inflammation, wound healing, analgesic actions Maresins (Fig. 1) are 12-LOX-derived metabolites of DHA produced mainly by macrophages via 13S,14S-epoxy-DHA intermediate. Maresin 1 (7R,14S-diHDHA, conjugated triene E,E,Z) displays potent anti-inflammatory, pro-resolving, analgesic and pro-healing actions [28,36,37]. 13,14-eMaR (13S,14S-epoxy-DHA, E,E,Z) inhibited leukotriene B4 formation and promoted conversion of M1 macrophages to M2 phenotype [38]. 22-hydroxy-Maresin 1 and 14oxo-Maresin 1 were recently identified in human leukocytes [39]. Maresin 1 younger sibling Maresin 2 (13R,14S-diHDHA, Z,E,E) reduces neutrophil infiltration and enhances efferocytosis as shown in human macrophages [40]. Sequential actions of 12-LOX and 5LOX on DHA generated 7S,14S-diHDHA (E,Z,E), which reduced polymorphonuclear leukocyte (PMNL) infiltration in zymosaninduced peritonitis [36]. The epoxide intermediate could also serve as a substrate for GSTM4 to yield the Maresin conjugates in tissue regeneration (MCTR) family, which are involved in regulation of host responses in clearing infections and promoting regeneration [41,42]. The Maresin family could be further expanded with the maresin-like mediators Maresin-L1 (14S,22-diHDHA) and MaresinL2 (14R,22-diHDHA) that were produced by leukocytes and platelets and are involved in wound healing [43]. Alternative u1oxidation of 14-HDHA by P450 produces 14S,21S-diHDHA; 14R,21R diHDHA; 14S,21R-diHDHA; and 14R,21S-diHDHA that also promoted wound healing [44], or anti-inflammatory 14S,20RdiHDHA [45]. 3.2. Protectins - resolution of inflammation, neuroprotection The most famous member of this family (Neuro)Protectin D1 (PD1; 10R,17S-diHDHA, E,E,Z) exhibits many beneficial effects (extensively reviewed in Refs. [28,35]). DHA is converted by 15-LOX to 16S,17S-epoxy-DHA intermediate that is either transformed to PD1 by enzymatic hydrolysis or reacted with GSH into Protectin conjugates in tissue regeneration (PCTR) family, namely 16glutathionyl-17-HDHA, 16-cysteinylglycinyl- 17-HDHA and 16cysteinyl-17-HDHA, with host-protective, proresolving, and tissue-regenerative actions [32](Fig. 2). Other members of the family are aspirin-triggered PD1 (AT-PD1, E,E,Z) [28,29] and PD1 metabolite 22-OH-PD1 (E,E,Z), which have been shown to exert potent proresolving actions by inhibiting PMNL chemotaxis [46]. Protectin DX (10S,17S-diHDHA, E,Z,E), an isomer of PD1 formed by consecutive sequential actions of two lipoxygenase reactions, belongs to a related family of poxytrins (PUFA oxygenated E,Z,E-conjugated triene) [47,48]. PDX inhibits human blood platelet aggregation [47], ROS production and cyclooxygenase activities in human neutrophils [49] and influenza virus replication [50,51]. 3.3. Resolvins - resolution of inflammation and wound healing

3. Oxygenated metabolites of DHA Besides the direct effects of DHA itself, indirect effects are mediated via its oxidation to potent lipid signaling molecules. DHA can be enzymatically oxidized to mono-, di- and tri-hydroxyDHA (HDHA), epoxy- and oxo-DHA metabolites, or modified by a free radical non-enzymatic mechanisms to neuroprostanes [27,29,30,34]. Many of HDHA derivatives belong to a family of SPMs,

The resolvin family members share 17-hydroxy residue introduced to DHA by 15-LOX (Fig. 2). There are 7 members, RvD1 (conjugated tetraene E,E,Z,E)e RvD6 and 17S-HDHA, showing many favorable biological effects such as stimulation of macrophage phagocytosis or inhibition of the production of pro-inflammatory cytokines [28,52]. Resolvins also participate in wound healing in mice [53,54]. As seen before, the intermediate 7S-hydroperoxy-

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O. Kuda / Biochimie 136 (2017) 12e20

Fig. 1. Schematic overview of the pathways related to maresins. diHDHA, dihydroxydocosahexaenoic acid; DPEP, dipeptidase; eMar, 13,14-epoxy-maresin; GGT, g-glutamyl transferase; GSH, glutathione; GSTM4, glutathione S-transferase; HpDHA, hydroperoxydocosahexaenoic acid; LOX, lipoxygenase; MCTR, Maresin conjugates in tissue regeneration; P450, cytochrome P450; sEH, soluble epoxide hydrolase. The bolded metabolites have been documented in humans.

17S-hydroxy-DHA could be coupled with GSH to form the Resolvin conjugates in tissue regeneration (RCTR) family [32]. Aspirintriggered (AT-) COX acetylation results in a production of the 17Rhydroxy residue family, called AT-resolvins, complementary to the 17S series, which exhibited anti-hyperalgesic effects in rats [55]. 3.4. Electrophilic oxo-derivatives (EFOX) of DHA e antiinflammatory, anti-proliferative effects EFOXs can be generated via enzymatic and nonenzymatic pathways and often serve as PPARg ligands (Fig. 3). 17-oxo-DHA and 13-oxo-DHA are generated by a COX-2-catalyzed mechanism in activated macrophages. These oxo-derivatives act as PPARg agonists and inhibit pro-inflammatory cytokine and nitric oxide production in macrophages [27]. The metabolite 17-oxo-DHA was later confirmed to be a PPARa/g dual covalent agonist and 4-oxo-DHA a selective PPARg agonist [26]. Moreover, EFOX form GSH conjugates after macrophage activation [27]. Besides COX-2, also 15-PGDH catalyzes the oxidation of HDHA to a,b-unsaturated oxo-DHA, namely 4-, 7-, 10-, 11-, 13-, 14-, 16-, 17-, and 20-oxo-DHA species. For instance, exogenous addition of 14-oxo-DHA to primary alveolar macrophages inhibited LPS-induced pro-inflammatory cytokine mRNA expression [30]. Furthermore, LOX-5 in human neutrophils generates 7-oxo-DHA [56], while 4-oxo-DHA was shown to inhibit cancer cell proliferation [57]. 3.5. Epoxides e anti-hypertensive, analgesic actions DHA may compete with arachidonic acid for conversion by cytochrome P450 (CYP2C/2J isoforms) to form epoxydocosapentaenoic acid (EDP or epoxy-DPA, Fig. 3). Among the family of EDPs [31], the metabolite 19,20-EDP (19,20-epoxy-DPA) seems to be the most significant member. It is a highly active anti-

arrhythmic agent [58], acts as a mediator of the anti-hypertensive effects of DHA in angiotensin-II dependent hypertension [59,60], or inhibits vascular endothelial growth factor (VEGF)- and fibroblast growth factor 2-induced angiogenesis, tumor growth, and metastasis via a VEGF receptor 2-dependent mechanism [61]. High hepatic levels of 19,20-EDP were associated with a reduction of tissue inflammation and lipid peroxidation [62]. A mixture of EPDs (7,8-EDP; 10,11-EDP, 13,14-EDP; 16,17-EDP and 19,20-EDP) exerted anti-hyperalgesic effects in animal models of pain associated with inflammation and diabetic neuropathy [31,63]. 3.6. Neuroprostanes e cardioprotection, wound healing Neuroprostanes (NP) are products of a free radical nonenzymatic peroxidation of DHA (Fig. 3). Based on the mechanism of formation and the stability of precursor radicals, the majority of NPs identified in vivo contains F-type prostane rings (F4-NPs) and belongs to 4-, or 20-series regioisomers, depending on the position of the hydroxyl group [34,64]. Among the F4-NPs, 4(RS)-4-F4tNeuroProstane showed the most active anti-arrhythmic properties [34] and other cardioprotective effects including a reduction of events such as arrhythmias and systolic cardiac failure were assigned to peroxidation products of DHA [65]. Also A4/J4-type NPs contribute to the anti-inflammatory actions of DHA metabolites as 14-A4-NP suppress the inflammatory response in macrophages via inhibition of NF-kB signaling [66]. Furthermore, a series of compounds termed Neuroketals can be generated via the NP pathway. These highly reactive g-ketoaldehydes (Neuroketals) react with primary amines, form lysyl-lactam protein conjugates via a pyrrole intermediate and were detected in human brain [67]. Similarly, when DHA esterified in phospholipids is cleaved by reactive oxygen species into 4-hydroxy-7-oxohept-5-enoic acid (HOHA), this product reacts with amino groups of proteins (lysines) and forms 2-

O. Kuda / Biochimie 136 (2017) 12e20

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Fig. 2. Schematic overview of the pathways related to protectins and resolvins. AT-, aspirin-triggered-; COX, cyclooxygenase; diHDHA, dihydroxydocosahexaenoic acid; GSH, glutathione; GST, glutathione S-transferase; HpDHA, hydroperoxydocosahexaenoic acid; LOX, lipoxygenase; P450, cytochrome P450; PGDH, hydroxyprostaglandin dehydrogenase; PCTR, Protectin conjugates in tissue regeneration; PD, protectin D; RCTR, Resolvin conjugates in tissue regeneration; RvD, resolvin D; sEH, soluble epoxide hydrolase; triHDHA, trihydroxydocosahexaenoic acid. The bolded metabolites have been documented in humans.

(u-carboxyethyl)pyrrole (CEP) adducts [68]. These CEPs are generated during inflammation, recognized by Toll-like-receptors 2 and CD36, and promote angiogenesis and wound healing [69e71]. Of note, DHA at low concentrations also prevents oxidative damage, while at high concentrations acts as a pro-oxidant [72].

4. Conjugates of DHA Besides oxidation, DHA can be conjugated with amines and alcohols to form amides and esters, respectively. See Fig. 4 for a schematic overview of the related pathways.

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Fig. 3. Schematic overview of the pathways related to oxygenated metabolites of docosahexaenoic acid (DHA). CEP, 2-(u-carboxyethyl)pyrrole; COX, cyclooxygenase; diHDHA, dihydroxydocosahexaenoic acid; diHDPA, dihydroxydocosapentaenoic acid; DPA, docosapentaenoic acid; GSH, glutathione; GST, glutathione S-transferase; HpDHA, hydroperoxydocosahexaenoic acid; HOHA, 4-hydroxy-7-oxohept-5-enoic acid; LOX, lipoxygenase; P450, cytochrome P450; PGDH, hydroxyprostaglandin dehydrogenase; ROS, reactive oxygen species; sEH, soluble epoxide hydrolase. The bolded metabolites have been documented in humans.

Fig. 4. Schematic overview of the pathways related to docosahexaenoic acid (DHA) conjugates. 13-DHAHLA, 13-(docosahexaenoyloxy)-hydroxylinoleic acid; 14-DHAHDHA, 14(docosahexaenoyloxy)-hydroxydocosahexaenoic acid; DHEA, docosahexaenoyl ethanolamine; DHG, docosahexaenoyl glycerol; diHDHEA, dihydroxy-DHEA; DPA, docosapentaenoic acid; HEDPEA, hydroxy-epoxy-docosapentaenoyl ethanolamine; HpDHEA, hydroperoxy-DHEA; LOX, lipoxygenase; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D; NAT, N-acyltransferase; PE, phosphatidylethanolamine; P450, cytochrome P450; The bolded metabolites have been documented in humans.

4.1. Ethanolamines and glycerol esters e neural development, immunomodulation, metabolic effects DHA is highly enriched in the brain and is metabolized to Ndocosahexaenoyl ethanolamine (DHEA, synaptamide). It is probably synthesized from DHA-containing phosphatidylethanolamine (DHA-PE) through acylation of phosphatidylethanolamine and subsequent liberation of DHEA by a specific phospholipase D. DHEA stimulates neurite growth, synaptogenesis, promotes differentiation of neural stem cells, and exhibited enhanced glutamatergic synaptic activity [73,74]. Administration of DHEA following lipopolysaccharide injection significantly reduced neuroinflammatory responses in the murine brain [75]. Its anti-inflammatory, immunomodulatory, and other beneficial metabolic effects were documented in macrophages and in adipose tissue [76e78], and it was also shown to enhance glucose uptake in myocytes [79] and activate PPARa [80]. Furthermore, DHEA can be oxidized to 10,17-

diHDHEA, 15-hydroxy-16,17-epoxy-docosapentaenoyl ethanolamine (15-HEDPEA), 13-HEDPEA, or 17S-DHEA with antiinflammatory and organ-protective effects [81,82]. Only little is known about the biology of docosahexaenoyl glycerol (1- or 2DHG) [83], but it could possibly serve as a DHA pool for 19,20EDP synthesis [60]. 4.2. Branched fatty acid esters of hydroxy fatty acids (FAHFA) e immunomodulation, resolution of inflammation There are currently three members of FAHFA family containing DHA: 9- and 13-DHAHLA in which DHA is esterified at the 9th and 13th carbon of hydroxy linoleic acid, and 14-DHAHDHA where DHA is esterified at the 14th carbon of 14-HDHA. We have recently demonstrated that 13-DHAHLA exerts strong anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of

O. Kuda / Biochimie 136 (2017) 12e20 Table 1 DHA metabolites identified in humans. DHA metabolites identified in humans

Human tissue

serum [110], milk [111], synovial fluid [112], leukocytes [39] Maresin 2, 13,14-epoxy- macrophages [40] maresin MCTRs lymph nodes, serum, plasma [42] Maresin-L1, Maresin-L2 leukocytes, platelets [43] Protectin D1 serum [110], cerebrospinal fluid [113,114], hippocampus [115], embryonic stem cells [116], breath condensates/lungs [117], milk [111] RvD1, RvD2 plasma, lymph tissue [110,118,119], adipose tissue [120,121], milk [111,122], cerebrospinal fluid [113,123] RvD3, RvD4 serum [103,110], milk [111] RvD5 synovial fluid [112] RCTRs, PCTRs spleen, macrophages [32] Neuroprostanes/ brain [67], retina [68], urine [124] Neuroketals/CEPs 19,20-EDP, 16,17-EDP plasma [119] DHEA blood [81,86] DHAHLA serum, adipose tissue [84] Maresin 1

zymosan particles [84]. 4.3. N-acyl amides - metabolic regulation, neuroprotection, neurotransmission Recently, an enzyme PM20D1 catalyzing condensation of fatty acids and amino acid (i.e. Phenylalanines) to N-acyl amides has been discovered [33], shedding light to the origin of these mediators which improve glucose homeostasis and increase energy expenditure. A group of N-acyl amides including N-docosahexaenoyl-Ser, Tyr, Trp, Gly, Pro, Val and Asp has been identified as modulators of vanilloid receptorerelated transient receptor potential (TRPV) channels [23]. The authors also noted that N-docosahexaenoyl amides are significantly more stable than other N-acyl amides and may even act as precursor molecules for the more reactive and fast-lived resolvins [23]. DHA could be also coupled with neurotransmitters to form i) N-docosahexaenoyl dopamine [85,86] that is capable of inducing PPARg-dependent breast cancer cell death [87]; ii) neuroprotective N-docosahexaenoyl serotonin [88] that was shown to inhibit glucagon-like peptide-1 secretion [89]; and iii) N-docosahexaenoyl GABA [23]. 5. Conclusion The purpose of this review was to summarize the knowledge about metabolites of DHA with documented biological activity and to illustrate their diversity. Many of the compounds listed above, especially non-enzymatic and P450 products, have been identified and tested only in-vitro and their structure with respect to chirality and configuration of double bonds was poorly explored. The stereochemistry is especially important for di- and tri-HDHA. Validation of these parameters by analytical methods and in vivo biological models is critical and the need is documented by the substitution of PD1 for PDX isomer [50], where the authors originally didn't differentiate between the isomers of 10,17-diHDHA [48,50,51]. Rigorous characterization of resolving E1 including stereochemical assignment, identification of biosynthetic pathway, receptor, and biological actions in cells, mice and humans illustrates the complexity of the research in the field of lipid mediators [90]. Total organic (stereoselective) synthesis, preferably coupled to biosynthesis, was achieved for Maresin 1 [91], Maresin 2 [92], eMaresin [38],MCTRs [41,42], 14,20- and 14,21-diHDHA [44,93],

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PD1, AT-PD1, PDX [94e96], 22-OH-PD1 [46], PCTRs [97,98], RvD1 and AT-RvD1 [99], RvD2 [100,101], RvD3 and AT-RvD3 [102], RvD4 [103], RvD5 and RvD6 [104,105], Neuroprostanes [106,107], etc. The interaction between biologists and organic chemists is crucial for full characterization of new bioactive lipids, but a demanding stereoselective synthesis (reviewed in Ref. [108]) complicates the process. Origin of the active metabolites adds another layer of complexity. Compounds synthesized locally via enzymes in small quantities and carrying a biological activity could be linked to a specific tissue or a cell type (e.g. maresins in macrophages), but metabolites formed by non-enzymatic reactions could be formed and act nearly anywhere at various concentrations. Their biological potency follows the same trend e spanning from picomolar concentrations for tightly controlled SPMs to micromolar levels for NPs. The biosynthetic machinery and its regulation in time and space represents the key difference between metabolites fulfilling criteria for autacoids and lipid mediators (e.g. SPMs [109]) and the other bioactive metabolites produced in response to oxidative stress (e.g. neuroprostanes) or lipids involved in general signal transduction. It is important to note that only a subgroup of DHA metabolites (Table 1) was identified in humans, either in tissues, isolated cells or fluids, and that their relevance to human pathology has to be explored in the future. The notion that high intake of omega-3 results in negative or off-target effects suggests that special attention should be paid to the bioavailability of omega-3. Comparison of different forms of omega-3 supplementation (seafood, triacylglycerols, phospholipids, ethyl esters, waxes, etc.) in the context of health and disease (metabolic diseases, cardiovascular and cancer risk factors, etc.) might lead to optimized strategies for each situation. Alternatively, targeted use of bioactive DHA metabolites or their analogs with prolonged metabolic stability could be a therapeutic approach in future. It is well documented that DHA and its metabolites have many beneficial effects on human health. However, it is clear that our knowledge of the receptors mediating direct effects of DHA and those of its diverse metabolites is incomplete. Importantly, given the chemical structure of DHA and the known multiple pathways of its metabolism, novel bioactive derivatives of this important fatty acid could be expected in future. Involvement of stereospecific organic synthesis and validation of biosynthetic pathways will be needed to undoubtedly assign biological effects to a specific metabolite. The obvious challenge will be to translate the beneficial effects of the newly discovered DHA-derived lipid mediators, which are observed at the molecular level, into clinical practice and into the new therapeutic strategies. Acknowledgements This study was supported by grants from the Czech Science Foundation (GA16-04859S) and the Ministry of Health of the Czech Republic (NV16-29182A). The author thanks N.A. Abumrad, M. Rossmeisl and J. Kopecky for critical reading of the manuscript and helpful suggestions. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.biochi.2017.01.002. References [1] D. Mozaffarian, R.N. Lemaitre, I.B. King, X. Song, H. Huang, F.M. Sacks, E.B. Rimm, M. Wang, D.S. Siscovick, Plasma phospholipid long-chain omega-

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