Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs

Melissa Gabbs; Shan Leng; Jessay G Devassy; Md Monirujjaman; Harold M Aukema

doi:10.3945/an.114.007732

. 2015 Sep 5;6(5):513–540. doi: 10.3945/an.114.007732

Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs^¹^,^²

Melissa Gabbs ^1,³, Shan Leng ^1,³, Jessay G Devassy ¹, Md Monirujjaman ¹, Harold M Aukema ^1,^*

PMCID: PMC4561827 PMID: 26374175

Abstract

Oxylipins formed from polyunsaturated fatty acids (PUFAs) are the main mediators of PUFA effects in the body. They are formed via cyclooxygenase, lipoxygenase, and cytochrome P450 pathways, resulting in the formation of prostaglandins, thromboxanes, mono-, di-, and tri-hydroxy fatty acids (FAs), epoxy FAs, lipoxins, eoxins, hepoxilins, resolvins, protectins (also called neuroprotectins in the brain), and maresins. In addition to the well-known eicosanoids derived from arachidonic acid, recent developments in lipidomic methodologies have raised awareness of and interest in the large number of oxylipins formed from other PUFAs, including those from the essential FAs and the longer-chain n–3 (ω-3) PUFAs. Oxylipins have essential roles in normal physiology and function, but can also have detrimental effects. Compared with the oxylipins derived from n–3 PUFAs, oxylipins from n–6 PUFAs generally have greater activity and more inflammatory, vasoconstrictory, and proliferative effects, although there are notable exceptions. Because PUFA composition does not necessarily reflect oxylipin composition, comprehensive analysis of the oxylipin profile is necessary to understand the overall physiologic effects of PUFAs mediated through their oxylipins. These analyses should include oxylipins derived from linoleic and α-linolenic acids, because these largely unexplored bioactive oxylipins constitute more than one-half of oxylipins present in tissues. Because collated information on oxylipins formed from different PUFAs is currently unavailable, this review provides a detailed compilation of the main oxylipins formed from PUFAs and describes their functions. Much remains to be elucidated in this emerging field, including the discovery of more oxylipins, and the understanding of the differing biological potencies, kinetics, and isomer-specific activities of these novel PUFA metabolites.

Keywords: oxylipin, polyunsaturated fatty acid, eicosanoid, lipid mediators, omega-3, omega-6, cyclooxygenase, lipooxygenase, cytochrome P450, lipidomics

Introduction

Oxylipins are PUFA oxidation products formed via one or more mono- or dioxygen-dependent reactions. They are major mediators of PUFA effects in the body, with the most well-known oxylipins being the eicosanoids formed from arachidonic acid (AA)⁴ (20:4n–6). Oxylipins also can be formed from other PUFAs, with the more common ones being octadecanoids derived from linoleic acid (LA) (18:2n–6) and α-linolenic acid (ALA) (18:3n–3), eicosanoids derived from dihomo-γ-linolenic acid (DGLA) (20:3n–6) and EPA (20:5n–3), and docosanoids derived from adrenic acid (AdA) (22:4n–6) and DHA (22:6n–3). The PUFA precursors to oxylipins can be obtained directly from the diet or from the elongation and desaturation of LA and ALA into longer-chain PUFAs. Hence, a high n–6 PUFA intake is generally associated with a high concentration of n–6 PUFA-derived oxylipins and a high n–3 PUFA intake is generally associated with a high concentration of n–3 PUFA-derived oxylipins.

However, the types of oxylipins produced from tissue PUFAs not only depend on the amount of dietary PUFAs consumed, but also on the amounts of competing PUFAs for incorporation into phospholipids and for elongation and desaturation to longer-chain PUFAs. Further, the oxygenases present for metabolizing these PUFAs into oxylipins in each tissue, as well as enzyme preferences for specific PUFAs, influence oxylipin production. Hence, the tissue oxylipin profile does not necessarily mimic dietary PUFA intake or tissue PUFA profile, necessitating the direct assessment of tissue oxylipins in order to understand the effects of PUFAs that are mediated via oxylipins. The recent advent of lipidomics methodologies has enabled the analyses of oxylipin profiles from all PUFA substrates simultaneously, raising awareness of the vast number of oxylipins in the body. Indeed, these analyses have shown that AA oxylipins comprise less than one-half of all oxylipins. Other studies have shown that oxylipins derived from PUFAs besides AA also have significant biological activity. This necessitates the investigation of the entire oxylipin profile in order to understand the overall effects of dietary PUFAs via their metabolism to oxylipins. Therefore, because there is currently no collated data on oxylipins in mammalian tissue, the purpose of this review is to provide a detailed compilation of the main oxylipins formed from the various PUFAs, and to provide a general overview of their functions.

Oxylipin Formation

Oxylipins are found throughout the body in all tissues, urine, and blood. Classically, they have been described as having a short half-life, acting locally, and not being stored, but being synthesized in situ when needed. However, not all oxylipins are short-lived, as evidenced by the steady-state concentrations of both free and esterified oxylipins in tissues such as the liver, adipose tissue, the kidney, and ileum (1–3). The free forms are presumably the biologically active oxylipins, but the functions of those that are found esterified to phospholipid are not known. It is possible that they may alter membrane properties or act as a storage reservoir.

Oxylipin formation begins with cell activation, which results in precursor PUFAs in the sn-2 position of membrane phospholipids being liberated by cytosolic phospholipase A₂ (cPLA₂) (4). Evidence for the importance of this enzyme is provided by findings from a patient lacking this enzyme, in whom liberation of free PUFAs and subsequent oxylipin formation is reduced compared with healthy controls (5, 6). However, although only AA oxylipins were examined in these studies, lack of cPLA₂ did not completely block oxylipin formation. A recent study showed that inhibition of adipose TG lipase in mast cells also reduced oxylipin formation (7). Because TGs typically contain only small amounts of AA, this raises the question of whether non-AA PUFAs might be released in greater amounts via alternate pathways, such as adipose TG lipase. Further studies examining whether PUFA liberation via this enzyme is a direct source of PUFAs for oxylipin biosynthesis, or whether TG lipase indirectly provides PUFAs for incorporation into phospholipid before liberation via cPLA₂ activity, remain to be carried out. Once formed, free oxylipins can mediate their biological effects via interactions with receptors or intracellular effectors, or can be re-esterified into lipids. In addition, small amounts of PUFAs esterified to phospholipid or cholesterol can be converted into oxylipins in situ (8, 9).

PUFA metabolism into oxylipins occurs by 3 main pathways, which are briefly described below. For more details on specific oxylipin generating enzymes, oxylipin receptors, and breakdown products of oxylipins, there are several excellent reviews (10–21).

Cyclooxygenase

The first oxylipin generation pathway involves cyclooxygenase (COX) enzymes, which convert PUFAs into prostanoids, i.e., PGs and thromboxanes (10–12). Prostanoids have one or more double bonds and a characteristic five-carbon ring structure at the 8- to 12-carbon positions of 20-carbon PUFA-derived oxylipins. COX converts DGLA, AA, EPA, and AdA into 1-, 2-, 3- and dihomo-2-series prostanoids, such as prostaglandin D₁ (PGD₁), PGD₂, PGD₃, and dihomo-PGD₂, respectively (22, 23). After the prostanoids are produced and released, they mediate their effects via binding to G protein–coupled receptors on the surface of cells, or other intracellular effectors, such as PPARγ (10, 12). The number of double bonds and the type of ring structure of a prostanoid determines its receptor specificity. There are 5 classes of prostanoid receptors, including receptors for PGD, PGE, PGI, PGF, and thromboxane A. Each of these receptors can have several isoforms, which may themselves have differing effects. They are characterized by their most potent biological ligand, but there is also some ligand crossreactivity with these receptors (12). In addition to the prostanoids, COX also can produce select hydroxy FAs [e.g., 11-hydroxy-eicosatetraenoic acid (11-HETE) from AA, 13-hydroxy-docosahexaenoic acid (13-HDoHE) from DHA, and 9-hydroxy-octadecadienoic acid (9-HODE) from LA] (24–27).

Lipoxygenase

The second pathway of oxylipin formation involves lipoxygenases (LOXs) that catalyze the formation of hydroxy FAs and their metabolites (including leukotrienes, lipoxins, resolvins, protectins, maresins, hepoxilins, and eoxins). There are multiple LOX enzymes that have traditionally been classified by the position of the hydroperoxy and hydroxy FAs they form from AA [e.g., 5-hydroperoxy-eicosatetraenoic acid (5-HpETE) and 5-HETE are formed from AA by 5-LOX activity]. This nomenclature has limitations because the position is different with PUFAs of differing chain length, some enzymes act at multiple positions, and there can be differences in the positional specificities of the same homolog in different species (11, 15). An alternative nomenclature is to use the gene names to describe the LOX enzymes (15).

Hydroxy FAs (e.g., 5-HETE) produced via LOX are further metabolized to their keto [(e.g., oxo-eicosatetraenoic acid (oxo-ETE)] or dihydroxy derivatives [e.g., 5,15-dihydroxy-eicosatetraenoic acid (5,15-DiHETE)]. 5-LOX activated by 5-lipoxygenase activating protein (FLAP) results in the production of leukotrienes, including leukotriene B₄ and those previously known as the slow reacting substance of anaphylaxis, the cysteinyl leukotrienes (19). Combinations of sequential LOX activities (and sometimes including epoxygenase and hydrolase activities) results in the formation of di- and tri-hydroxy FAs, which includes the lipoxins, resolvins, protectins, and maresins (14, 16). Hepoxilins also are formed from 12-HpETE (21) and eoxins from 15-HpETE (28). As with prostanoids, the LOX-derived oxylipins also appear to mediate their effects by binding to G protein–coupled receptors and intracellular effectors, although receptors for all oxylipins have not been identified.

Cytochrome P450

The third pathway of PUFA metabolism to oxylipins involves a diverse array of membrane-bound cytochrome P450 (CYP) enzymes that are so named because of their unique absorbance at 450 nm when reduced and bound by carbon monoxide. Originally known for their roles in xenobiotic metabolism, there are over 50 CYP enzymes expressed in humans, divided into multiple families and subfamilies based on amino acid identity (11). CYP enzymes that form oxylipins can have epoxygenase or ω-hydroxylase activity. For example, they can convert AA, EPA, and DHA into epoxy-eicosatrienoic acid (EpETrE), epoxy-eicosatetraenoic acid (EpETE), and epoxy-docosapentaenoic acid [(EpDPE), sometimes abbreviated EDP] respectively, via epoxygenase, and HETE, hydroxy-eicosapentaenoic acid (HEPE), and HDoHE, respectively, via ω-hydroxylase activity. Epoxygenase products are rapidly metabolized via soluble epoxide hydrolase (sEH) to form dihydroxy FAs such as the AA, EPA, and DHA metabolites dihydroxy-eicosatrienoic acid (DiHETrE), DiHETE, and dihydroxy-docosapentaenoic acid, respectively. Similar to oxylipins formed via the other pathways, these oxylipins also mediate their effects via specific receptors or by crossreacting with other oxylipin receptors (11, 13, 17, 18). In addition, they may also enter cells and mediate effects intracellularly by modulating transcription factors and ion channels (13).

PUFA Substrates for Oxylipin Formation

Oxylipins are formed from a number of n–3 and n–6 PUFA precursors, such as the n–6 PUFAs AA, LA, γ-linolenic acid (GLA), DGLA, and AdA, and the n–3 PUFAs ALA, stearidonic acid, EPA, and DHA. Although studies indicate that cPLA₂ exhibits preference for AA and EPA (29, 30), the presence of oxylipins from other PUFAs demonstrates that they can be released in sufficient quantities for oxylipin production. Pathways are shown in the figures and are described by the PUFA precursors below.

N–6 PUFAs

Arachidonic acid.

AA produces 2-series oxylipins (Figure 1) via the COX pathway, initially resulting in the formation of PGG₂ and subsequently to PGH₂, which is then rapidly converted to other PGs (e.g., PGF_2α) and thromboxanes (e.g., thromboxane A₂) via specific PG and thromboxane synthases (20). As is the case with the other oxylipins, prostanoids are then rapidly degraded to numerous inactive and active metabolites, some of which can be used as markers of the parent compound, whereas others can mediate the same or opposite effects ascribed to the parent compounds (31–33).

AA also produces oxylipins via the LOX pathway, resulting in HpETEs, (e.g., 12-HpETE), which are further rapidly converted to hydroxy FAs via glutathione peroxidase (34). 5-, 12-, and 15-HETE are the most commonly described HETEs in mammals, although 8-, 9-, and 11-HETE also are produced, and sometimes in greater amounts (35, 36). The 11- or 15-HETE isomers also can be produced via COX activity, as indicated above (24, 25). HETE can be further converted to oxo-ETE via dehydrogenase activity (37, 38), or to DiHETE via further COX (e.g., 5,11-DiHETE), LOX (e.g., 5,15-DiHETE), or CYP ω-hydroxylase (e.g., 5,20-DiHETE) activity (39, 40). In addition, the HpETE formed via LOX can be metabolized via several other routes: 5-HpETE can be further converted to 4-series leukotrienes (e.g., leukotriene C₄) via 5-LOX after activation by FLAP; 12-HpETE can be isomerized to hepoxilins (e.g., hepoxilin B₃) and subsequently converted to trioxilins (e.g., trioxilin B₃) (21, 41); and 15-HpETE can be converted to eoxins (e.g., eoxin C₄) (28). Moreover, lipoxins (e.g., lipoxin A₄) can be formed from 5- or 15-HpETE via further LOX activity (42–44). Epi-lipoxin (e.g., 15-epi-lipoxin A₄) formation can also be initiated by aspirin-acetylated or nitrosylated COX2 and 5-LOX (45–47). AA also can be converted nonenzymatically to HETE (48) and isoprostanes (e.g., iso-PGF_2α) (49). The latter are often used as a marker of oxidative stress in vivo; for further discussion of these nonenzymatic oxylipins, see the review by Musiek et al. (49).

AA metabolism via CYP ω-hydroxylase activity results in the formation of HETE with the hydroxy group being at the omega or methyl end of the FA (e.g., 20-HETE), whereas CYP epoxygenase activity yields epoxy FAs (e.g., 14,15-EpETrE), which can be converted to dihydroxy FAs (e.g., 14,15-DiHETE) via sEH activity, as reviewed in several articles (13, 17, 18). Formation of other HETEs (e.g., 13-HETE) may be mediated via CYP bisallylic hydroxylase activity (50–52), but the importance of this pathway is less known.

Linoleic acid.

Although the size of the literature for LA oxylipins (Figure 2) is markedly smaller than that for most other oxylipins (especially AA oxylipins), LA oxylipins are usually present in tissues and blood in higher amounts than oxylipins derived from any other PUFA (53–55). LA produces oxylipins through the LOX pathway, resulting in hydroperoxy FAs, which are rapidly converted to hydroxy FAs (e.g., 13-HODE), which can be further metabolized to keto FAs (e.g., 13‑oxo-octadecadienoic acid) (56, 57). LA also can be metabolized via the epoxygenase activity of CYP, resulting in epoxygenated FAs [e.g., 9,10-epoxy-octadecenic acid (9,10-EpOME)], which are metabolized via sEH activity to form dihydroxy FAs (e.g., 9,10-dihydroxy-octadecenoic acid) (58). Further, LA can be converted to trihydroxy FAs (e.g., 9,10,13-trihydroxy-octadecenoic acid) potentially by sequential metabolism of LOX and epoxygenase activity and/or auto-oxidation (59). Several other LA oxylipins also can be produced nonenzymatically (e.g., 9-HODE) (60). There also are reports that the formation of a small amount of the LA oxylipins may be mediated via COX (e.g., 9-HODE) (27, 61) or CYP bisallylic hydroxylation (e.g., 17-HODE) (50–52) activity; the relative importance of these pathways remains to be elucidated.

γ-Linolenic acid.

GLA can be converted via LOX to 10- and 13-hydroxy-octadecatrienoic acid(γ) [13-HOTrE(γ)] (62) in human platelets and via CYP to γ-6,7-, γ-9,10-, and γ-12,13-epoxy-octadecadienoic acid by human CYP enzymes in vitro (63). Other oxylipins derived from GLA (e.g., 6-HOTrEγ) have been reported to be synthesized in vitro in a patent application (64). Note that oxylipins derived from GLA are distinguished from ALA oxylipins with the use of the γ notation.

Dihomo-γ-linolenic acid.

DGLA (Figure 3) can be converted via COX to 1-series PGs (e.g., PGI₁) and thromboxanes (e.g., thromboxane A₁) (22, 65, 66) via LOX to yield hydroperoxy (e.g., 15-hydroperoxy-eicosatrienoic acid) and hydroxy FAs [e.g., 15-hydroxy-eicosatrienoic acid (15-HETrE)] (67–72), and via CYP epoxygenase and sEH to epoxy-eicosadienoic acid (e.g., 8,9-epoxy-eicosadienoic acid) and dihydroxy-eicosadienoic acid (e.g., 8,9- dihydroxy-eicosadienoic acid) (68, 69, 73).

Adrenic acid.

AdA (Figure 4) can be metabolized by COX into dihomo-prostaglandins such as dihomo-PGE₂, dihomo-thromboxane B₂, and dihomo-PGI₂ (74–79). Metabolism via the LOX pathway generates hydroxy-docosatetraenoic acids (also referred to as dihomo-HETE) such as 17-hydroxy-docosatetraenoic acid (dihomo-17-HETE), which can be further converted to dihydroxy compounds (e.g., dihomo-10,17-DiHETE) (76–78), and via the CYP pathway to dihomo-EpETrE (epoxy-docosatrienoic acids) such as dihomo-16,17-EpETrE, which can be further converted to their respective dihydroxy compounds e.g., (dihomo-16,17-DiHETrE) (76).

n–3 PUFAs

α-Linolenic acid.

ALA produces oxylipins (Figure 5) via the LOX pathway, resulting in hydroxy FAs (e.g., 9-HOTrE), which can be further metabolized to keto FAs (e.g., 9-oxo-octadecatrienoic acid) (80). As with LA, there are reports that indicate that HOTrE may be formed via COX activity, but the importance of this pathway in vivo remains to be determined (27). ALA also can be metabolized via CYP epoxygenase activity, resulting in epoxygenated FAs, (e.g., 12,13-epoxy-octadecadienoic acid) (63), which can be further converted to dihydroxy FAs (e.g., 12,13-dihydroxy-octadecadienoic acid) via sEH activity (54). Other ALA metabolites that have been reported include 18-HOTrE from ALA via CYP activity (18), 9,16-dihydroxy-octadecatrienoic acid via LOX activity (80), and 12-HOTrE via COX2 activity (27).

Stearidonic acid.

Oxylipins derived from stearidonic acid (e.g., 13-hydroxy-octadecatetraenoic acid) have been reported to be produced in vitro in a patent application (64).

Eicosapentaenoic acid.

Similarly to AA, EPA produces oxylipins (Figure 6) via the COX pathway, yielding 3-series PGs (e.g., PGE₃) and thromboxanes (e.g., thromboxane A₃) (23). Compared with AA, EPA is generally a poorer substrate for COX, particularly for the COX1 isoform (81). EPA can produce hydroperoxy FAs (e.g., 5-hydroperoxy-eicosapentaenoic acid), which can be further converted to hydroxy FAs (e.g., 5-HEPE) by LOX activity (23, 82, 83), and 5-series leukotrienes (e.g., leukotriene B₅) via combined 5-LOX and FLAP activity (83, 84). HEPE such as 5-HEPE also can be metabolized to dihydroxy-eicosapentaenoic acids such as 5,12-dihydroxy-eicosapentaenoic acid (85) or to keto FAs such as 5-oxo-eicosapentaenoic acid (86). Metabolites of other HEPE isomers are likely to be present, but few have been identified. Hydroxy FAs from EPA with hydroxy groups on the 18–20-carbon positions also are formed via ω-hydroxylase activity of the CYP pathway (e.g., 18-HEPE) (87, 89). The 18-HEPE formed via this pathway (as well as by acetylated COX2) can be further converted to the E-series resolvins (e.g., resolvin E1) via 5-LOX activity (40, 43, 89). EPA can also produce epoxy FAs (e.g., 14,15-EpETE) via CYP epoxygenase activity (90), which can be further converted to dihydroxy FAs (e.g., 14,15-DiHETE) by sEH (91). As with AA and LA, bisallylic hydroxylation of EPA can also yield HEPEs, such as 10-HEPE (92).

Docosahexaenoic acid.

DHA (Figure 7) can be metabolized via the LOX pathway to hydroxy FAs (e.g., 4-HDoHE) with a hydroperoxy intermediate [e.g., 4-hydroperoxy-docosahexaenoic acid (4-HpDoHE) (93)]. 14-HpDoHE can be further metabolized to form maresins (e.g., maresin 1) (94), and 17-HpDoHE can be metabolized to 17-HDoHE, or to resolvins (e.g., resolvin D1) and protectins (e.g., protectin D1) via further LOX and epoxygenation steps. Protectin D1 is produced via LOX, epoxide formation from the hydroperoxide product, and epoxide hydrolase activity (95) while protectin DX is formed via double LOX activity (96). 17-HpDoHE derived from DHA also can be produced via aspirin-acetylated COX2, yielding the aspirin-triggered resolvins (e.g., aspirin-triggered resolvin D1) and aspirin-triggered protectins (e.g., aspirin-triggered protectin D1) (26, 97, 98). DHA also has been shown to yield hydroxy FAs nonenzymatically (e.g., 8-HDoHE) (99, 100), and 13-HDoHE can be formed via COX2 (26). Recent studies provide evidence that HDoHE also can be metabolized to dihydroxy-docosahexaenoic acid (DiHDoHE) (e.g., 14,20-DiHDoHE) (101) and keto FAs (e.g., 7-oxo-docosahexaenoic acid) (102), with more likely to be demonstrated in the future. Oxylipins can be produced from DHA via CYP epoxygenase activity, yielding epoxy FAs (e.g., 16,17-EpDPE) (90, 93), which can be converted to dihydroxy FAs (16,17-dihydroxy-docosapentaenoic acid) via sEH (91). CYP ω-hydroxylase activity produces HDoHE with hydroxy groups near the methyl end of DHA (e.g., 21-HDoHE) (93).

DHA-derived oxylipins. 13-HDoHE also is produced via the COX pathway (26). 14,21-DiHDoHE also may be formed from 21-HDoHE (313, 314). ASA, acetylsalicylic acid; AT, aspirin-triggered; COX, cyclooxygenase; CYP, cytochrome P450; DiHDoHE, dihydroxy-docosahexaenoic acid; DiHDPE, dihydroxy-docosapentaenoic acid; EpDPE, epoxy-docosapentaenoic acid; HDoHE, hydroxy-docosahexaenoic acid; HpDoHE, hydroperoxy-docosahexaenoic acid; LOX, lipoxygenase; MaR, maresin; oxo-DoHE, oxo-docosahexaenoic acid; PD, protectin; Rv, resolvin.

Oxylipin Functions

Oxylipins have a wide range of functions, many of which are still being elucidated. In addition, oxylipins derived from different pathways, as well as different substrate PUFAs, can have similar or opposing effects, necessitating knowledge of the overall oxylipin profile in order to understand their overall biological effects. Their functions are many, including apoptosis, tissue repair, blood clotting, cell proliferation, blood vessel permeability, pain, inflammation, immune actions, and blood pressure regulation (11, 87). General functions of oxylipins are described below and examples of functions are provided in Tables 1–7.

TABLE 1.

Examples of arachidonic acid–derived oxylipin functions¹

Arachidonic acid–derived oxylipin functions
COX oxylipins
PGA₂	Contributes along with PGE₂ to the development of Th1-type immune responses, with PGE₂ being more potent in human monocyte–derived dendritic cells (103)
	Inhibits Ca²⁺-stimulated ATPase activity of Walker-256 tumor microsomal membranes (104)
	Represses insulin-like growth factor I gene expression in C6 rat glioma cells (105)
PGB₂	Mediates mesenteric vascular dose-dependent vasodilatory and vasoconstrictory effects in animal models (106)
PGB₂	Elevates blood pressure, tracheal segment pressure, and bronchial resistance in guinea pigs (107)
PGD₂	Inhibits induced apoptosis in human articular chondrocytes (108)
	Inhibits murine lung inflammation (109)
	Promotes sleeping behavior (110)
	Regulates body temperature in rodent models (111, 112)
	Inhibits tumor cell proliferation in human cells and rodent model (113)
	Modulates synaptic transmission via D-type prostanoid receptor (116)
	Proinflammatory at nanomolar concentrations and anti-inflammatory at micromolar concentrations [reviewed in (34)]
	Inhibits human neutrophil activation in vitro (115, 116)
	Causes apoptosis of human eosinophils (117)
	Activates human eosinophils (118)
	Inhibits human platelet aggregation (119, 120)
PGE₂	Vasodilates cat cerebral arterioles (121)
	Potentiates human platelet aggregation at lower concentrations and inhibits aggregation at a higher concentrations (122)
	Induces human colon cancer cell growth (123)
	Stimulates IL-10 production in bone marrow–derived dendritic cells in murine model (124)
	Mediates lung inflammation in human cells (125)
15-keto-PGE₂	Activates PPARγ to enhance adipogenesis of murine 3T3-L1 cells (126)
6-keto-PGF_1α	Stable degradation product of PGI₂ and useful marker of PGI₂ in humans (127, 128)
9α,11β-PGF₂	Activates murine eosinophils (129)
PGF_2α	Mediates inflammatory tachycardia in the mouse (130)
	Initiates parturition in the mouse (131)
	Vasoconstricts rat brain arterioles (132)
13,14-dihydro-15-keto-PGF_2α	Reflects in vitro PGF_2α biosynthesis and is the main inactive degradation product of PGF_2α in humans (133)
PGI₂	Inhibits ADP-induced hamster platelet aggregation (134)
	Induces coronary vasodilation in dogs (135)
	Inhibits adhesion of human eosinophils to lung endothelial monolayers and transendothelial migration (136)
	Inhibits erythrocyte adhesion to bovine aortic endothelial cells (137)
PGJ₂	Causes apoptosis of human eosinophils (117)
PGJ₂	Induces respiratory burst in human eosinophils (118)
Δ¹²-PGJ₂	Releases eosinophils from guinea pig bone marrow and induces respiratory burst in human eosinophils (118)
Δ¹²-PGJ₂	Causes apoptosis of human eosinophils and neutrophils (117)
15-deoxy- Δ¹²,¹⁴-PGJ₂	Inhibits induced apoptosis in human articular chondrocytes (108)
	Anti-inflammatory via inhibition of NF-κB activation in human and monkey cell culture (138)
	Causes apoptosis of human eosinophils and neutrophils (117)
	Induces respiratory burst in human eosinophils (118)
	Reduces apoptosis in activated human and murine T-lymphocytes (139)
TxA₂	Mediates inflammatory tachycardia in the mouse (130)
	Causes irreversible platelet aggregation in human platelet-rich plasma (140)
	Stimulates mitogenesis of coronary artery smooth muscle cells in guinea pig model (141)
	Mediates hypertension in hypertensive rats (142)
	Vasoconstricts rabbit aorta (143)
TxB₂	Has a weak bronchoactive effect in guinea pigs and dogs (144)
	Increases systemic vascular resistance but does not cause platelet aggregation in dogs (145)
	Chemotactic in human peripheral PMN (146)
2,3-dinor-TxB₂	Marker of thromboxane synthesis in urine of rats (147, 148)
	Possible urinary marker of acute myocardial infarction in humans (149)
	Urinary marker for platelet activation (152)
11-dehydro- TxB₂	Plasma and urinary marker of thromboxane synthesis in human and rabbit models (35, 153, 154)
11-dehydro- TxB₂	Possible urinary marker of acute myocardial infarction in humans (149)
LOX oxylipins
5,15-DiHETE	Possesses weak human neutrophil and eosinophil chemotactic activity (153, 154)
8,15-DiHETE	Possesses weak human eosinophil chemotactic activity (153)
8,15-DiHETE	Exhibits chemotactic activity comparable to that of LtB₄ for human PMN (155)
12,20-DiHETE	Activates cholesterol ester hydrolysis in human vasculature (156)
Eoxins	Eoxin C₄, D₄ and E₄ all increase permeability of endothelial cell monolayer from human eosinophils and mast cells in vitro (28)
5-HETE	Inhibits the clonal proliferation of chick embryo fibroblasts and granulocytic progenitors (157)
	Stimulates human eosinophil chemotaxis and chemokinesis (158)
	Stimulates human neutrophil chemokinesis and enhances chemotactic responses (159, 160)
	Induces human neutrophil degranulation (161)
	Inhibits PGI₂ production in porcine coronary artery endothelial cells (162)
	Inhibit selenium-induced apoptosis in human prostate cancer cells; 12- and 15-HETE have no effect (163)
	Stimulates proliferation of human cancer cells at low concentrations (164)
	Promotes bovine neutrophil chemotaxis in vitro more potently than 5-HEPE (165)
5-HpETE	Inhibits human platelet aggregation similarly to 5-HpEPE, but less potently than 12- or 15-HpETE (166)
5-oxo-ETE	Stimulates human neutrophils and eosinophils (86, 167)
	Inhibits selenium-induced apoptosis in human prostate cancer cells, with one-half the potency of 5-HETE (163)
	Stimulates proliferation of human cancer cells in low concentrations and inhibits proliferation at higher concentrations (164)
	Promotes chemotaxis and raises cytosolic calcium concentrations in human neutrophils; more potent than 5-HETE, 15-oxo-ETE, and 5,15-DiHETE (154)
	Stimulates human neutrophils more potently than 5-HETE (168)
	Does not inhibit LOX enzyme activity (compared to 12- and 15-oxo-ETE) in vitro (169)
8-HETE	Stimulates human neutrophil chemokinesis and enhances chemotactic responses (159)
	Promotes wound healing via epithelial cell migration in rat cornea (36)
	Induces differentiation of murine 3T3-L1 preadipocytes (170)
9-HETE	Stimulates human eosinophil chemotaxis and chemokinesis (158)
9-HETE	Stimulates human neutrophil chemokinesis and enhances chemotactic responses (159)
11-HETE	Stimulates human eosinophil chemotaxis and chemokinesis (158)
	Stimulates human neutrophil chemokinesis and enhances chemotactic responses (159, 160)
	Inhibits human vascular smooth muscle cell proliferation (171)
11-oxo-ETE	Inhibits human colorectal adenocarcinoma epithelial and umbilical vein endothelial cell proliferation in culture (172)
12-HETE	Stimulates human neutrophil chemokinesis and enhances chemotactic responses (159)
	Induces human neutrophil degranulation (161)
	Increases rat heart mitochondrial calcium and nitric oxide, leading to oxidative stress and apoptosis (173)
	Increases monocyte adhesion to human endothelial cells leading to aortic fatty streak formation (174, 175)
	Enhances tumor cell adhesion to endothelial cells in mice (176)
	Enhances thrombin-induced aggregation (177), but suppresses collagen-induced aggregation of bovine platelets (178)
	Inhibits U-46619–induced aggregation of human platelets (179, 180)
	Reduces ADP-induced aggregation of mouse platelets (181)
	Stimulates erythrocyte adhesion to bovine aortic endothelial cells (137)
12-HpETE	Inhibits human platelet aggregation similarly to 12-HpEPE, and more potently than 5- or 15-HpETE (166, 182)
12-oxo-ETE	Selectively inhibits LOX enzyme activity in vitro (169)
12-oxo-ETE	Activates human neutrophils (183)
15-HETE	Exhibits vasodilation or vasoconstriction in isolated arteries from the guinea pig, rabbit, rat, and human, depending on species and conditions (184)
	Activates PPARγ in human and PPARβ/δ in mouse (185, 186)
	Inhibits human PMN migration across cytokine-activated endothelium in vitro (187)
	Inhibits degranulation and superoxide production in stimulated human PMN (188)
	Mediates hypoxia-induced rabbit pulmonary hypertension (189)
	Enhances thrombin-induced human platelet aggregation (190)
	Stimulates erythrocyte adhesion to bovine aortic endothelial cells (137)
15-HpETE	Exhibits vasodilation or vasoconstriction in isolated arteries from the guinea pig, rabbit, rat, and human, depending on species and conditions (184)
	Stimulates erythrocyte adhesion to bovine aortic endothelial cells (137)
	Induces migration of monocyte-like HL-60 cells across a human endothelial cell monolayer (191)
	Induces loss of rat cardiomyocyte membrane integrity (192)
	Inhibits human platelet aggregation similarly to 15-HpEPE, but less potently than 12-HpETE (166)
15-oxo-ETE	Selectively inhibits human LOX enzyme activity in vitro (169)
	Inhibits human vascular vein endothelial cell proliferation (193)
	Prevents apoptosis of rat pulmonary arterial smooth muscle cells (194)
HxA₃	Activates human neutrophils (195)
	Recruits human PMN to the site of inflammation (196)
	Promotes murine 3T3-L1 preadipocyte differentiation (197)
HxB₃	Promotes murine 3T3-L1 preadipocyte differentiation (197)
LtB₄	Releases human PMN lysosomal enzymes (198)
	Induces human PMN chemotaxis and aggregation (199, 200)
	Stimulates guinea pig lung strip contraction, but less potently than LtC₄ (201)
	Promotes chemotaxis of bovine neutrophils more potently than LtB₅ (165)
20-OH-LtB₄	Stimulates human neutrophil migration, but less potently than LtB₄ (202)
20-OH-LtB₄	Stimulates guinea pig lung strip contraction, but less potently than LtC₄ (201)
20-COOH-LtB₄	Stimulates human neutrophil migration, but less potently than LtB₄ (203)
20-COOH-LtB₄	Stimulates guinea pig lung strip contraction, but less potently than LtC₄ (201)
LtC₄	Causes guinea pig uterine and lung contractions (203)
	Stimulates guinea pig lung strip contraction more potently than LtB₄ (201)
	Mediates human skin inflammation (204)
	Increases permeability of endothelial cell monolayers from human eosinophils and mast cells in vitro (28)
	Contracts guinea pig lung parenchymal strips and ileal tissues, with similar potency to LtC₅ (205)
LtD₄	Enhances responsiveness to histamine in bovine airway smooth muscle (206)
	Causes guinea pig uterine and lung contraction (203)
	Mediates human skin inflammation (204)
	Increases permeability of endothelial cell monolayers from human eosinophils and mast cells in vitro (28)
LtE₄	Causes guinea pig uterine and lung contraction (203)
LtE₄	Coronary constrictor in the in situ pig heart (207)
LtF₄	Induces bronchoconstriction in the guinea pig, but less actively than LtD₄ (208)
LxA₄	Inhibits LtB₄-induced human PMN activation (209)
	Stimulates human monocyte migration and adhesion (210)
	Inhibits zymosan A–induced peritonitis in mice (211)
	Promotes corneal epithelial cell wound healing in mice (212)
	Increases renal plasma flow and glomerular filtration rate in the rat (213)
	Stimulates phospholipid remodeling without causing aggregation in human neutrophils (214)
	Antagonizes LtD₄-induced lowering of glomerular filtration rate in the rat (215)
	Induces contraction of isolated guinea pig pulmonary smooth muscle (similar to LxA₅ and LxB₄ effects), and vasorelaxation of rat or guinea pig aortic rings (similar to LxB₄) (216)
	Inhibits proliferation of human A549 cells, but less potently than 15-epi LxA₄, 15-epi LxB₄ or LxB₄ (45)
LxB₄	Stimulates human monocyte migration and adhesion (210)
	Decreases renal plasma flow and glomerular filtration rate in the rat (213)
	Inhibits zymosan A-induced peritonitis in mice (211)
	Stimulates phospholipid remodeling without causing aggregation in human neutrophils (214)
	Induces contraction of isolated guinea pig pulmonary smooth muscle (similar to LxA₄ and LxA₅ effects), and vasorelaxation of rat or guinea pig aortic rings (similar to LxA₄) (216)
	Inhibits proliferation of human A549 cells, but less potently than 15-epi LxB₅ (45)
15-epi LxA₄	Inhibits leukocyte-endothelium interactions in mice (217)
	Blocks reactive oxygen species generation in human endothelial cells (218)
	Stimulates human monocyte chemotaxis (219)
	Inhibits proliferation of human A549 cells, but less potently than 15-epi LxB₅ (45)
15-epi LxB₄	Inhibits proliferation of human A549 cells more potently than 15-epi LxA₄ or LxB₄ (45)
CYP oxylipins
5,6-DiHETrE	Vasodilates pre-constricted pressurized mouse arteries more potently than its EpETrE isomer (220)
5,6-DiHETrE	Hyperpolarizes rat vascular smooth muscle from rat small coronary arteries by activating BK channels (221)
8,9-DiHETrE	Vasodilates pre-constricted pressurized mouse arteries more potently than its EpETrE isomer (220)
	Vasodilates isolated canine coronary arterioles more potently than EpETrE isomers (222)
	Hyperpolarizes rat vascular smooth muscle from rat small coronary arteries by activating BK channels (221)
11,12-DiHETrE	Vasodilates pre-constricted pressurized mouse arteries more potently than its EpETrE isomer (220)
	Vasodilates isolated canine coronary arterioles more potently than EpETrE isomers (222)
	Hyperpolarizes rat vascular smooth muscle from rat small coronary arteries by activating BK channels (221)
	Relaxes porcine coronary artery with similar potency as its EpETrE isomer (223)
14,15-DiHETrE	Vasodilates preconstricted pressurized mouse arteries more potently than its EpETrE isomer (220)
	Vasodilates isolated canine coronary arterioles more potently than EpETrE isomers (222)
	Hyperpolarizes rat vascular smooth muscle from rat small coronary arteries by activating BK channels (221)
	Most potent PPARα activator in a monkey COS-7 cell expression system when compared to other DiHETrE and EpETrE isomers (224)
	Stimulates metastasis and escape from tumor dormancy in several murine tumor models (225)
5,6-EpETrE	Vasodilatory effects in intestinal microcirculation in rat model (226)
	Promotes angiogenesis by stimulating endothelial cell proliferation in vitro and angiogenesis in vivo in murine model (227)
	Vasodilates isolated canine coronary arterioles less potently than DiHETrE isomers (222)
	Vasodilates pre-constricted pressurized mouse arteries less potently than its DiHETrE isomer (220)
8,9-EpETrE	Promotes angiogenesis by stimulating endothelial cell proliferation in vitro and angiogenesis in vivo (227)
	Dilates coronary microvessels with similar potency to other EpETrE isomers as well as EpETE and EpDPE isomers in canine and porcine models (228)
	Attenuates cell apoptosis in rat heart myocytes after hypoxia and reoxygenation (229)
	Vasodilates isolated canine coronary arterioles less potently than DiHETrE isomers (222)
	Vasodilates preconstricted pressurized mouse arteries less potently than its DiHETrE isomer (220)
11,12-EpETrE	Vasodilatory effects in intestinal microcirculation (226)
	Dilates coronary microvessels with similar potency to other EpETrE isomers as well as EpETE and EpDPE isomers in canine and porcine models (228)
	Inhibits vascular inflammation distinct from its vasodilatory effects by inhibiting NF-κB and inhibitor of κ B kinase in murine model (230)
	Attenuates cell apoptosis in rat heart myocytes after hypoxia and reoxygenation (229)
	Vasodilates isolated canine coronary arterioles less potently than DiHETrE isomers (222)
	Vasodilates preconstricted pressurized mouse arteries less potently than its DiHETrE isomer (220)
	Relaxes porcine coronary artery with similar potency as its DiHETrE isomer (223)
	Enhances angiogenesis and tumor progression in murine model (231)
14,15-EpETrE	Dilates coronary microvessels with similar potency to other EpETrE isomers as well as EpETE and EpDPE isomers in canine and porcine model (228)
	Attenuates cell apoptosis in rat heart myocytes after hypoxia and reoxygenation (229)
	Vasodilates U-46619–preconstricted bovine coronary artery rings more potently than 14,15-DiHETrE (232)
	Vasodilates isolated canine coronary arterioles less potently than DiHETrE isomers (222)
	Vasodilates preconstricted pressurized mouse arteries less potently than its DiHETrE isomer (220)
	Antinociceptive effect in thermally produced tail-flick response in rats, whereas other regioisomers were not effective at same dose (233)
	Enhances angiogenesis and tumor progression (231)
16-HETE	Induces vasodilation in isolated rabbit kidney (234)
	Inhibits human leukocyte activation (235)
	Decreases intracranial pressure in a rabbit model of stroke (235)
17-HETE	Inhibits rabbit proximal tubule ATPase activity, but has no renal vasodilatory activity (234)
18-HETE	Induces vasodilation in isolated rabbit kidney (234)
19-HETE	Reduces pressure in rabbit-perfused kidneys (236)
	Induces vasodilation in canine renal arteries (237)
	Stimulates rat renal Na⁺/K⁺-ATPase (238)
20-HETE	Reduces pressure in rabbit-perfused kidneys (236)
	Induces vasoconstriction in canine renal arteries (239) and porcine coronary arteries (239)
	Stimulates inflammatory cytokine production in human endothelial cells (240)
	Stimulates proliferation of rat vascular smooth muscle cells (241)

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ADP, adenosine diphosphate; ATPase, adenosine triphosphatase; BK, big potassium; COX, cyclooxygenase; CYP, cytochrome P450; DiHETE, dihydroxy-eicosatetraenoic acid; DiHETrE, dihydroxy-eicosatrienoic acid; EpDPE, epoxy-docosapentaenoic acid; EpETE, epoxy-eicosatetraenoic acid; EpETrE, epoxy-eicosatrienoic acid; HEPE, hydroxy-eicosapentaenoic acid; HETE, hydroxy-eicosatetraenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; HpETE, hydroperoxy-eicosatetraenoic acid; Hx, hepoxilin; LOX, lipoxygenase; Lt, leukotriene; Lx, lipoxin; oxo-ETE, oxo-eicosatetraenoic acid; PMN, polymorphonuclear leukocyte; Th, T-helper; Tx, thromboxane.

TABLE 7.

Examples of DHA-derived oxylipin functions¹

DHA-derived oxylipin functions
LOX oxylipins
14,20-DiHDoHE	Inhibits PMN infiltration in the mouse peritonitis model (101)
14,21-DiHDoHE	Enhances wound healing in murine models (313, 314)
4-HDoHE	Inhibits endothelial cell proliferation and sprouting angiogenesis in mouse model of oxygen-induced retinopathy (315)
7-HDoHE	Activates PPARγ in transfected monkey kidney COS-7 cells (316)
13-HDoHE	Inhibits TNFα-induced cytokine production in human microglial cells (26)
14-HDoHE	Inhibits human platelet aggregation (180)
17S-HDoHE	Vasodilates bovine coronary arterial smooth muscle cells (317)
17S-HDoHE	Reduces genotoxic and oxidative damage in murine hepatocyte cells and TNFα release by murine macrophages (316)
17R-HDoHE	Inhibits hyperalgesia in a rat model of adjuvant-induced arthritis (318)
	Has anti-inflammatory effects in a mouse model of dextran sulfate sodium-induced colitis (319)
	Inhibits TNFα-induced cytokine production in human microglial cells (26)
17-HDoHE	Decreases LPS-induced TNFα secretion in a murine macrophage cell line (304)
17-HDoHE	Inhibits 5-LOX in rat basophilic leukemia cells (82)
17-HpDoHE	Displays cytotoxic potency in human neuroblastoma cells (320)
MaR1	Anti-inflammatory in a murine model of acute respiratory distress syndrome (321)
	Reduces inflammation- and chemotherapy-induced neuropathic pain in mice (322)
	Mitigates inflammatory effects of LPS-induced lung injury in mouse model (323)
PD1	Reduces genotoxic and oxidative damage in murine hepatocyte cells and TNFα release by murine macrophages (316)
	Promotes murine phagocyte removal during acute inflammation in vitro and in vivo (318)
	Decreases leukocyte accumulation in a mouse model of kidney injury (324)
	Protects human retinal pigment epithelial cells from apoptosis due to oxidative stress (325)
	Promotes mouse corneal epithelial cell wound healing (212)
PDX	Reduces inflammation in murine peritonitis and inhibits human microglial cell cytokine expression in vitro (91)
	Inhibits collagen-, AA-, and thromboxane-induced human platelet aggregation (326)
	Inhibits PMN infiltration in mouse model of ischemic stroke (327)
	Decreases reactive oxygen species production and COX activity in human neutrophils (328)
	Improves insulin sensitivity by raising muscle IL-6 without affecting adipose tissue inflammation in a murine model (329)
RvD1	Reduces reactivity and Ca²⁺ sensitivity in overactive human pulmonary artery smooth muscle cells (330)
RvD1	Improves bacterial clearance and survival of mice with cecal ligation and puncture-induced sepsis (331)
RvD2	Has anti-inflammatory effects in a mouse model of dextran sulfate sodium–induced colitis (319)
	Improves bacterial clearance and survival of mice with cecal ligation and puncture-induced sepsis (332)
	Inhibits inflammatory pain in mice (333)
	Mitigates neutrophil-mediated damage in mouse burn model (334)
RvD3	Reduces peritonitis and dermal inflammation in murine model (335)
RvD5	Enhances phagocyte containment of Escherichia coli in a mouse model (336)
AT-RvD1	Inhibits hyperalgesia in a rat model of adjuvant-induced arthritis (318)
AT-RvD1	Has anti-inflammatory effects in a mouse model of dextran sulfate sodium-induced colitis (319)
AT-RvD3	Reduces murine peritonitis and dermal inflammation with activity similar to RvD3 (335)
CYP oxylipins
7,8-, 10,11-, 13,14-, 16,17-, 19,20-DiHDPE	Inhibit human platelet aggregation with moderately lower potency to EpDPE, and do not affect thromboxane synthesis (298)
13,14-, 16,17- DiHDPE	Reduce pain associated with inflammation more potently than EpETrE and EpEPE (91)
13,14-DiHDPE	Markedly reduces potency to dilate porcine coronary arterioles compared with parent compound (339)
7,8-, 10,11-, 13,14-, 16,17-, 19,10-EpDPE	Dilates porcine coronary arterioles (337)
7,8-, 10,11-, 13,14-, 16,17-, 19,10-EpDPE	Inhibits human platelet aggregation and thromboxane synthesis, with potency similar to other EpETE and EpDPE isomers, and greater potency than EpETrE isomers (298)
16,17-, 19,20-EpDPE	Inhibits Met-1 tumor angiogenesis and growth in mice (231)
19,20-EpDPE	Decreases human platelet aggregation (299)

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AA, arachidonic acid; AT, aspirin-triggered; COX, cyclooxygenase; CYP, cytochrome P450; DiHDoHE, dihydroxy-docosahexaenoic acid; DiHDPE, dihydroxy-docosapentaenoic acid; EpDPE, epoxy-docosapentaenoic acid; EpEPE, epoxy-eicosapentaenoic acid; EpETE, epoxy-eicosatetraenoic acid; EpETrE, epoxy-eicosatrienoic acid; HDoHE, hydroxy-docosahexaenoic acid; HpDoHE, hydroperoxy-docosahexaenoic acid; LOX, lipoxygenase; MaR, maresin; PMN, polymorphonuclear leukocyte; Rv, resolvin.

n–6 PUFA oxylipin functions

COX oxylipins.

The most well known oxylipins are eicosanoids derived from the n–6 PUFA AA (Table 1). COX-derived prostanoids are involved in the regulation of blood pressure, reproduction, diuresis, blood platelet aggregation, modulation of the immune and nervous systems, gastric secretions, cancer, inflammation, and the stimulation of smooth muscle contraction, among other effects, as reviewed in several articles (10, 12, 338–340). Within these COX metabolites there can be similar and differing effects on these functions. For example, PGI₂ is an antiaggregatory factor for platelets (341), whereas thromboxane A₂ serves as a proaggregatory factor (342). Another example is the vasodilatory effect of PGI₂ and PGE₂, and the vasoconstrictory effect of PGF_2α in some vascular beds (135, 343). PGE₂ also can have effects on thrombosis that vary depending on the receptor it interacts with. For example, PGE₂ can bind either the EP3 receptor, which makes PGE₂ a prothrombotic mediator, or EP4, which makes PGE₂ an antithrombotic mediator (344). Similarly, PGD₂ and its metabolites can be both proinflammatory and be involved in the resolution of inflammation (32). Compared with COX products formed from AA, those derived from DGLA (Table 3) are usually, but not always, less active or produced less efficiently (345). For example, PGE₁ is less stimulatory of aortic smooth muscle cell proliferation than PGE₂ (346). The AdA metabolites (Table 4) dihomo-PGE₂ and dihomo-PGI₂ also are inactive or much less active compared with their AA analogs with respect to their platelet aggregating activity and contractile properties in both vascular and nonvascular smooth muscle (77, 347).

TABLE 3.

Examples of dihomo-γ-linolenic acid–derived oxylipin functions¹

Dihomo-γ-linolenic acid–derived oxylipin functions
COX oxylipins
PGD₁	Activates proinflammatory receptor chemoattractant receptor homologous molecule expressed on T helper type 2 cells/D prostanoid receptor in human kidney cells (compared to PGE₁) (262)
PGD₁	Inhibits human platelet aggregation, but is 1% as potent as PGD₂ or PGD₃ (119)
PGE₁	Does not activate proinflammatory receptor CRTH2/DP2 in human kidney cells (compared to PGD₁) (262)
	Reduces healing time of lower limb ulcers in human patients (263)
	Alleviates neurologic deteriorations of diabetic rats (264)
	Vasodilates rat coronary and systemic circulation (265)
	Stimulates peripheral blood flow in humans with peripheral arterial disease (266)
	Reduces pulmonary hypertension in patients with pulmonary arterial hypertension (267)
	Inhibits human platelet aggregation (120, 268)
13,14-dihydro-PGE₁	Inhibits human platelet aggregation with similar potency to PGE₁ (268)
LOX oxylipins
12-HETrE	Enhances delayed-type hypersensitivity in guinea pig model (269)
12-HETrE	Inhibits human platelet aggregation (270)
15-HETrE	Inhibits epidermal hyperproliferation in guinea pig skin (67, 271)
	Inhibits formation of proinflammatory LtB₄ in human neutrophils (70)
	Inhibits cellular growth and AA metabolism in human prostatic adenocarcinoma cells (272)

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AA, arachidonic acid; COX, cyclooxygenase; HETrE, hydroxy-eicosatrienoic acid; LOX, lipoxygenase; Lt, leukotriene.

TABLE 4.

Examples of adrenic acid–derived oxylipin functions¹

Adrenic acid–derived oxylipin functions
COX oxylipins
Dihomo-PGE₂	Stimulates cAMP production in rabbit renal medullary interstitial cells more potently than dihomo-PGI₂, but 10 times less potently than PGE₂ (77)
Dihomo-PGE₂	No contractile activity in vascular and nonvascular smooth muscle tissue at levels at which PGE₂ had significant activity (77)
Dihomo-PGI₂	Inhibits thrombin-induced human platelet aggregation, but is 1% as potent as PGI₂ (75)
Dihomo-PGI₂	Stimulates cAMP production in rabbit renal medullary interstitial cells, but 100 times less potently than PGI₂ (77)
Dihomo-TxA₂	No contractile activity in rabbit aorta (79) [compared with constrictory effect of TxA₂ (143)]
CYP oxylipins
Dihomo-7,8-, Dihomo-10,11-, Dihomo-13,14-, and Dihomo-16,17-EpETrE	Induce vasorelaxation in bovine coronary arterial rings (79)
	Dilate canine and porcine coronary microvessels with similar potency to other dihomo-EpETE isomers, as well as EpETrE and EpEPE isomers (228)
Dihomo-16,17-EpETrE	Causes concentration-related relaxations in preconstricted bovine adrenal cortical arteries (76)

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COX, cyclooxygenase; CYP, cytochrome P450; EpEPE, epoxy-eicosapentaenoic acid; EpETE, epoxy-eicosatetraenoic acid; EpETrE, epoxy-eicosatrienoic acid; Tx, thromboxane.

LOX oxylipins.

LOX products such as 5-, 12-, and 15-HETE derived from AA and secreted by epithelial cells and leukocytes are involved in many chronic diseases such as inflammation, obesity, cardiovascular disease, kidney disease, and cancer (348–352) (Table 1). As is the case with COX metabolites, AA-derived LOX products can have effects that are both similar to and differing from each other, as well as from those derived via the COX and CYP pathways. For example, 12-HETE has been shown to have both pro- and antithrombotic effects (179, 353, 354), whereas thromboxane A₂ is prothrombotic (342) and PGI₂ is antithrombotic (341). LOX-derived HETEs and their oxo-ETE metabolites appear to be primarily proinflammatory; e.g., 5-HETE has chemotactic roles in polymorphonuclear leukocytes (PMNs) and rabbit alveolar macrophages (162, 355, 356) and stimulates specific granule release from human neutrophils (161). Both 5-oxo-ETE and 12-oxo-ETE also can stimulate eosinophils and neutrophils, but appear to have less activity than their corresponding HETEs (154, 357). 5-HETE can also be further converted to 4-series leukotrienes (e.g., leukotriene C₄) that play an important role in inflammation, asthma, and allergies (358). Eoxins formed from 15-HpETE also have proinflammatory effects (28), and hepoxilins and their metabolites (trioxilins) are another group of oxylipins derived from 12-HpETE that are involved in neutrophil migration and intracellular calcium release (195, 196).

It is important to note, however, that some AA-derived oxylipins also display anti-inflammatory and anticancer activity. For example, 15-HETE can inhibit degranulation of PMNs, superoxide production, and endothelial PMN interaction (187, 188). In addition, 15-HETE can be metabolized to lipoxins, which can be synthesized by epithelial cells and leukocytes and modulate response to injury by mediating apoptosis and resolution of inflammation, in addition to decreasing pain, angiogenesis, and cell proliferation (14, 42, 359). Aspirin-triggered lipoxins (e.g., 15-epi-lipoxin A₄) are formed via aspirin-acetylated COX2 and 5-LOX and have similar properties to the lipoxins (360, 361).

In addition to AA metabolites, LOX also metabolizes other n–6 PUFAs, including LA, GLA, DGLA and AdA (Tables 2–4). As with AA oxylipins, 9-HODE and 13-HODE derived from LA mostly have been related to pathologic conditions such as atherosclerosis, nonalcoholic steatohepatitis, and Alzheimer disease (362–364), but there are also instances in which HODEs and their oxo-octadecadienoic acid metabolites are anti-inflammatory and antiproliferative (176, 271, 365). Although no functions for GLA oxylipins have been reported, DGLA oxylipins also tend to antagonize the analogous LOX-derived AA oxylipins. For example, PGE₁ and 15-HETrE from DGLA have antiproliferative effects, inhibit cancer cell growth, and inhibit bleomycin-induced lung fibrosis (366–368), whereas 15-HETrE has anti-inflammatory effects on skin (271). Three-series leukotrienes derived from DGLA may also reduce inflammation and broncho-constriction because of their relatively lower production compared with 4-series leukotrienes from AA and possibly lower bioactivity (369, 370).

TABLE 2.

Examples of linoleic acid–derived oxylipin functions¹

Linoleic acid–derived oxylipin functions
LOX oxylipins
9-HODE	Induces endoplasmic reticulum stress in human macrophages (242)
	Inhibits proliferation and induces apoptosis in human U937 cells (243)
	Proinflammatory in skin under oxidative conditions in human (244)
	Induces maturation, scavenger receptor expression and activates PPARγ-dependent transcription in human monocytes (245)
	Does not inhibit tumor cell adhesion to endothelial cells (compared to 13-HODE) in mice (176)
9-oxo-ODE	Activates PPARγ-dependent transcription in human monocytes (as do 9-HODE and -HpODE) (245)
13-HODE	Prevents platelets from adhering to human vascular endothelium (246)
	Decreases thrombin-induced platelet adherence to other platelets and to endothelial cells in vitro (247)
	Induces maturation and scavenger receptor expression and activates PPARγ-dependent transcription in human monocytes (245)
	Inhibits proliferation of hyperproliferative skin in guinea pigs (248)
	Inhibits tumor cell adhesion to endothelial cells (176)
	Inhibits the secretion and assembly of TG-rich lipoprotein particles in vitro (249)
	Inhibits human neutrophil production of LtB₄ in vitro (70)
13-HpODE	Relaxes canine circumflex and splenic arteries, similarly to 13-HODE (250)
13-HpODE	Relaxes human pulmonary arteries (184)
13-oxo-ODE	Reduces inflammation in human colonic epithelial cells (251)
	Does not inhibit tumor cell adhesion to endothelial cells (compared to 13-HODE) in mice (176)
	Does not inhibit LOX enzyme activity (compared to 12- and 15-oxo-ETE) in vitro (169)
	Activates PPARγ-dependent transcription in human monocytes (as do 13-HODE and -HpODE) (245)
CYP oxylipins
9,10-DiHOME	Decreases left ventricular–developed pressure recovery and increases coronary resistance after ischemia/reperfusion in the mouse heart (252)
9,10-DiHOME	Causes mitochondrial dysfunction, leading to cell death in rabbit renal proximal tubular cells, whereas parent epoxy compound is not toxic (253)
12,13-DiHOME	Causes mitochondrial dysfunction, leading to cell death in rabbit renal proximal tubular cells, whereas parent epoxy compound is not toxic (253)
	Causes acute respiratory distress syndrome in mice; more toxic than its epoxy parent (254)
	Lacks protective effect of 12,13-EpOME in rabbit renal proximal tubular cells exposed to hypoxia/reoxygenation (255)
9,10-EpOME	Inhibits mitochondrial respiration in perfused rat lung (256)
	Relaxes rat stomach smooth muscle and uncouples mitochondrial respiration (257)
	Induces canine heart failure when injected intravenously (258)
	Inhibits growth of normal and transformed human cells in culture (259)
	Induces vasoconstriction in isolated perfused cat carotid arteries (260)
12,13-EpOME	Pretreatment with low concentrations maintains mitochondrial respiration in rabbit renal proximal tubular cells exposed to hypoxia/reoxygenation; 12,13-DiHOME has no effect (255)
	Induces vasoconstriction in isolated perfused cat carotid arteries (260)
	Induces dysfunction in isolated rabbit renal cortical mitochondria, whereas 12,13-DiHOME does not (261)

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CYP, cytochrome P450; DiHOME, dihydroxy-octadecenoic acid; EpOME, epoxy-octadecenoic acid; HODE, hydroxy-octadecadienoic acid; HpODE, hydroperoxy-octadecadienoic acid; LOX, lipoxygenase; Lt, leukotriene; oxo-ETE, oxo-eicosatetraenoic acid; oxo-ODE, oxo-octadecadienoic acid.

CYP oxylipins.

Oxylipins derived via the CYP pathway from AA include EpETrE and HETE, which have vascular, cardiac and renal functions (13, 371, 372). The effects of these oxylipins also are unique and can be opposing. For example, AA-derived EpETrEs formed via CYP epoxygenase have hypotensive effects, which is opposite to the hypertensive effects of 20-HETE formed via ω-hydroxylase activity (237, 373). In addition, 16-, 18-, and 19-HETE, as well as 20-HETE metabolites (20-COOH-AA and 20-OH-PGE₂), also can promote vasodilation (234, 237, 374, 375). In some cases, the DiHETrE metabolites of EpETrE formed via sEH activity have less activity (232), but in other cases the DiHETrE have similar or even greater potency (220, 222). Interestingly, sEH inhibitors are currently being used to treat hypertension pharmacologically by prolonging the effects of the epoxy FAs on vasodilation (376), but polymorphisms in the CYP enzymes that produce EpETrE do not consistently correlate with effects on hypertension, as reviewed in Bellien and Joannides (377). In addition, EpETrEs also play roles in many other biological functions, such as insulin sensitivity (378), hyperalgesia (91), and tumor angiogenesis and metastasis (225, 231).

CYP oxylipins formed from LA appear to have effects similar to those derived from AA. For example, 9,10- and 12,13-EpOME derived from LA are produced by neutrophils and macrophages, mediating inflammatory effects (379, 380) (Table 2). These oxylipins were originally referred to as leukotoxin and isoleukotoxin, respectively, but later studies indicate that their toxic effects may be due to conversion by sEH to their diol metabolites (381). Elevated EpOME also has been related to extensive burns, respiratory syndrome, and systemic organ failure in burned skin of humans and lung (382).

n–3 PUFA oxylipin functions

In general, but not always, oxylipins formed from n–3 PUFAs have lesser biological potency when compared with those derived from n–6 PUFAs, and often compete for the same receptor, further dampening the biological effect (383). In addition, because they also compete with n–6 PUFAs for the same oxylipin biosynthetic enzymes, they may reduce biological activity by reducing the amount of total and n–6 PUFA–derived oxylipins produced and increasing concentrations of less active n–3 PUFA–derived oxylipins (286, 384).

COX oxylipins.

With respect to COX oxylipins, those derived from EPA are similar to DGLA oxylipins, generally being less potent or produced less efficiently (286) than the analogous oxylipins derived from AA (Table 6). Hence, compared with PGE₂, PGE₃ binds to the EP4 receptor with less affinity and activity in colorectal cancer cells (383) and demonstrates less mitogenetic and inflammatory activity in fibroblasts and monocytes (280, 383, 385). Compared with thromboxane A₂, thromboxin A₃ is produced less efficiently and was reported to have less vasoconstrictory and aggregatory activity (286), but a later study has attributed this reduced biological effect to the presence of PGD₃ in the incubations and found that thromboxane A₂ and thromboxane A₃ have similar aggregatory activities (81). PGI₃ and PGI₂ also have similar vasodilatory and antiaggregatory effects on platelets (286) and thromboxane A₂ and thromboxane A₃ have a similar ability to elevate plasma catecholamines in rats or to activate the thromboxane receptor (81, 283, 286, 384).

TABLE 6.

Examples of EPA-derived oxylipin functions¹

EPA-derived oxylipin functions
COX oxylipins
15-deoxy-PGJ₃	Increases adiponectin secretion from murine adipocytes (276)
PGD₃	Lowers intraocular pressure in rabbit model (277)
	Decreases peripheral vascular resistance and increases cardiac output and heart rate in dogs (278)
	As potent as PGD₂ in modulating sympathetic nerve transmission in the eye but less effective in activating vagally mediated bradycardia in cat model (279)
	Inhibits human platelet aggregation with similar or greater activity than PGD₂ (119, 120)
PGE₃	Lowers intraocular pressure but caused mild conjunctival hyperemia in rabbit model (277)
	Compared with PGE₂, is not mitogenic to and is less efficient in inducing COX2 gene expression in murine NIH 3T3 fibroblasts, and less efficient in inducing IL-6 synthesis in murine RAW 264.7 macrophages (280)
	Inhibits proliferation of human A549 cells (281) and mouse melanoma B16 cells (282)
	Less effective than PGE₂ in elevating plasma noradrenaline when administered intracerebroventricularly in rats (283)
	Less potent stimulator of cAMP production than PGE₂ in HEK293 human renal cells (81)
PGF_3α	Less protective than PGF_2α on ethanol induced gastric mucosal injury in rat model (284)
PGI₃	Inhibits aggregation in human and rabbit platelets (285, 286)
PGI₃	Promotes relaxation of bovine coronary arteries (286)
Δ¹²-PGJ₃	Inhibits progression of leukemia in a mouse model (287)
TxA₃	Synthesized at a much lower rate than TxA₂ in human platelets (286)
	Elevates catecholamines when administered intracerebroventricularly as potently as TxA₂ in rats (283)
	Activates human platelet aggregation with potency comparable with TxA₂ (81)
LOX oxylipins
5-HEPE	Enhances glucose-dependent insulin secretion in mouse MIN6 insulinoma cells and human NuTu80 intestinal carcinoma cells (288)
5-HEPE	Promotes bovine neutrophil chemotaxis in vitro, but less potently than 5-HETE (165)
5-HpETE	Inhibits human platelet aggregation, but less effectively than 12-HpEPE (166)
5-oxo-EPE	Stimulates migration of both human neutrophils and eosinophils at one-tenth the activity of 5-oxo-ETE (86)
8-HEPE	Induces adipogenesis in mouse preadipocytes and glucose uptake in myoblasts via PPAR activation (2)
9-HEPE	Induces adipogenesis in mouse preadipocytes and glucose uptake in myoblasts via PPAR activation (2)
12-HEPE	Inhibits human platelet aggregation similarly to 12-HETE, but less effectively than 12-HpEPE or 12-HpETE (166)
12-HpEPE	Inhibits human platelet aggregation similarly to 12-HpETE, and more potently than 5- or 15-HpEPE (166, 182)
15-HEPE	Inhibits 5-LOX in rat basophilic leukemia cells (84)
15-HEPE	Inhibits cellular growth and AA metabolism in human prostatic adenocarcinoma cells (272)
15-HpEPE	Inhibits human platelet aggregation similarly to 15-HpETE, but less potently than 12-HpEPE (166)
	Inhibits glucosamine synthetase activity in rabbit gastric mucosa (289)
	Decreases rabbit renal PG synthesis (290)
	Inhibits AA metabolism in rabbit platelets (291)
LtA₅	Inhibits the formation of LtB₄ from LtA₄ by rat and human neutrophil LtA₄ hydrolase (292)
LtB₅	Less active than LtB₄ in aggregating rat and human neutrophils (83)
LtB₅	Promotes chemotaxis of bovine or human neutrophils, but is much less potent than LtB₄ (165, 205)
LtC₅	Contracts guinea pig lung parenchymal strips and ileal tissues with potency similar to LtC₄ (205)
	Inhibits the anaphylactic reaction in guinea pig isolated heart, with potency similar to LtC₄ (293)
	Contracts guinea pig ileum but less potently than LtC₄ (294)
LtD₅	Inhibited IL-1β–induced COX2 expression in human pulmonary microvascular endothelial cells (295)
LtD₅	Stimulates volume regulation in murine Ehrlich ascites tumor cells (similar potency as LtD₄) (296)
LxA₅	Induces contraction of isolated guinea pig pulmonary smooth muscle (similar to LxA₄ and LxB₄ effects), but does not induce vasorelaxation of rat or guinea pig aortic rings (unlike LxA₄ and LxB₄) (216)
LxA₅	Induces superoxide anion generation from canine neutrophils and contraction of rat tail arteries (297)
LxB₅	Does not induce contraction of isolated guinea pig pulmonary smooth muscle (unlike LxA₅, LxA₄, and LxB₄) or vasorelaxation of rat or guinea pig aortic rings (unlike LxA₄ and LxB₄) (216)
LxB₅	Induces superoxide anion generation from canine neutrophils (with similar activity to 4-series Lx) (297)
CYP oxylipins
8,9-, 11,12-, 14,15-, 17,18-DiHETE	Inhibit human platelet aggregation, but with much less potency than parent EpETE (298)
8,9-, 11,12-, 14,15-, 17,18-EpETE	Dilate canine and porcine coronary microvessels with similar potency to other EpETE isomers as well as EpETrE and dihomo-EpETrE isomers (228)
8,9-, 11,12-, 14,15-, 17,18-EpETE	Inhibit human platelet aggregation and thromboxane synthesis with potency similar to other EpETE and EDPE isomers and potency greater than EpETrE isomers (298)
17,18-EpETE	Decreases human platelet aggregation (299)
	Relaxing effect on human bronchi arterial and airway smooth muscles (300)
	Anti-inflammatory effect in human lungs (301)
	Vasodilator in rat vascular smooth muscle cells (302)
18-HEPE	Inhibits macrophage-mediated inflammation in cardiac fibroblasts in culture and prevents pressure overload–induced cardiac fibrosis and inflammation in mice (303)
18-HEPE	Decreases LPS-induced TNFα secretion in the murine macrophage cell line (304)
RvE1	Reduces dermal inflammation, peritonitis, dendritic cell migration, and IL-12 production in an inflammatory mouse model (305)
	Reduces total leukocytes and PMN infiltration in murine peritonitis (306)
	Reduces hepatic fibrosis in murine model of infection (307)
	Promotes phagocyte removal during acute inflammation in vitro and in vivo (308)
RvE2	Stops zymogen-induced PMN leukocyte infiltration in murine peritonitis (309)
	Enhances phagocytosis and anti-inflammatory cytokine production in murine peritonitis (310)
	Inhibits human neutrophil infiltration and proinflammatory cytokines in an acute peritonitis (311)
RvE3	Inhibits neutrophil chemotaxis in vitro and reduces neutrophil numbers in zymosan-induced murine peritonitis in vivo (89)
RvE3	Blocks PMN infiltration in a mouse model of peritonitis (312)

Open in a new tab

AA, arachidonic acid; COX, cyclooxygenase; CYP, cytochrome P450; diHETE, dihydroxy-eicosatetraenoic acid; EpETE, epoxy-eicosatetraenoic acid; EpETrE, epoxy-eicosatrienoic acid; HEPE, hydroxy-eicosapentaenoic acid; HETE, hydroxy-eicosatetraenoic acid; HpEPE, hydroperoxy-eicosapentaenoic acid; HpETE, hydroperoxy-eicosatetraenoic acid; LOX, lipoxygenase; Lt, leukotriene; Lx, lipoxin; oxo-EPE, oxo-eicosapentaenoic acid; oxo-ETE, oxo-eicosatetraenoic acid; PMN, polymorphonuclear leukocyte; Rv, resolvin; Tx, thromboxane.

LOX oxylipins.

LOX also metabolizes the n–3 PUFAs, ALA to HOTrE, EPA to HEPE and DHA to HDoHE, oxylipins that also tend to have less inflammatory activity or to be anti-inflammatory (Tables 5–7). There is very little information on ALA-derived oxylipins, but recent findings indicate that 9,16-dihydroxy-octadecatrienoic acid has anti-inflammatory and antiaggregatory effects by reducing PG production (80), and that 9- and 13-HOTrE are associated with reduced glomerular hypertrophy in obese rats (55). An earlier paper indicates that 13-HOTrE may have anti-inflammatory effects in chondrocytes (273), and a recent paper showed that 13-oxo-octadecatrienoic acid can stimulate glucose uptake and differentiation in adipocytes (275). EPA oxylipins have been investigated much more and are primarily anti-inflammatory; for example, 5-hydroperoxy-eicosapentaenoic acid can be metabolized to leukotriene B₅, which has less activity and also competes with leukotriene B₄ and therefore reduces inflammation and broncho-constriction (386–388). 5-oxo-eicosapentaenoic acid derived from 5-HEPE is 10% as potent in stimulating neutrophils than the AA oxylipin (5-oxo-ETE) derived from 5-HETE (86). 15-HEPE derived from EPA also exhibits anticancer effects. For example, in human prostatic adenocarcinoma cells, 15-HEPE can inhibit cancer cell growth and inhibit production of AA oxylipins (272).

TABLE 5.

Examples of α-linolenic acid–derived oxylipin functions¹

α-Linolenic acid–derived oxylipin functions
COX oxylipins
9-HOTrE	Associated with glomerular hypertrophy in obese rats (55)
9,16-diHOTrE	Inhibits PG synthesis from COX1 and collagen-induced human platelet aggregation (80)
13-HOTrE	Suppresses IL-1β–induced expression of matrix metalloproteinases in human chondrocytes in vitro (273)
13-HOTrE	Associated with glomerular hypertrophy in obese rats (55)
13-HpOTrE	Causes moderate and reversible depression in action potential markers in rat cardiomyocytes (274)
13-oxo-OTrE	Induces glucose uptake and promotes adipocyte differentiation in murine model (275)
CYP oxylipins
9,10-DiHODE	Lower in blood of hyperlipidemic vs. normolipidemic persons (54)
12,13-DiHODE	Lower in blood of hyperlipidemic vs. normolipidemic persons (54)

Open in a new tab

COX, cyclooxygenase; CYP, cytochrome P450; diHODE, dihydroxy-octadecadienoic acid; diHOTrE, dihydroxy-octadecatrienoic acid; HOTrE, hydroxy-octadecatrienoic acid; HpOTrE, hydroperoxy-octadecatrienoic acid; oxo-OTrE, oxo-octadecatrienoic acid.

DHA also is metabolized via LOX, resulting in the production of HDoHE, which also generally exhibits beneficial effects. For example, 4-HDoHE has been reported to inhibit proliferative retinopathy and retinal endothelial cell proliferation (315) and 14-HDoHE can antagonize platelet activation and smooth muscle constriction (180, 389). The functions of 14-HDoHE may be mediated via maresins, given that they have been shown to be involved in resolution of inflammation, tissue regeneration, and analgesia (94, 390), or via other DiHDoHEs, which have similar protective effects, such as the wound healing properties of 14,21-DiHDoHE in mice (313) and the inhibition of PMN infiltration in a mouse peritonitis model by 14,20-DiHDoHE (101). Similarly, 17-HDoHE inhibits 5-LOX in rat leukemia cells (82), reduces inflammation and oxidative damage in murine hepatocyte injury (316), and has antihyperalgesic properties in a rat model of arthritis (318). Some of these actions may be via the D-series resolvins and protectins derived from 17-HpDoHE. Resolvins have been shown to have protective actions in inflammatory diseases (97, 391, 392), whereas the effects of protectins vary by isomer—protectin DX has antiaggregatory effects (326, 393) and can restore insulin sensitivity in obese mice (329), but protectin D1 does not exhibit these activities (329, 394). Both can inhibit influenza virus replication (395, 396), reduce inflammation, and accelerate the resolution of inflammation (392), with the latter study indicating that protectin D1 has greater potency in this regard. Helpful reviews delineating differences in structure and functions of the protectins can be found in 2 articles (18, 97).

CYP oxylipins.

n–3 PUFA oxylipins derived via the CYP pathway also have some similar and some differing effects compared with their n–6 PUFA–derived counterparts (Tables 5–7). EpETEs derived from EPA have vasodilatory and anti-inflammatory effects (339, 399, 400), which is similar to EpETrE derived from AA, with the vasodilatory effects of EpETE possibly exceeding those of EpETrE in some vascular beds (337, 398). In addition, several CYP isoforms preferentially metabolize n–3 over n–6 PUFAs, as reviewed in 2 articles (87, 399). EpETE can also inhibit Ca²⁺ and isoproterenol-induced contractility of neonatal cardiomyocytes, suggesting that they have antiarrhythmic effects (400). EpDPE derived from DHA has anti-inflammatory, vasodilatory, and anticancer effects, similar to EpETE (231, 299, 337). EpDPE also can inhibit angiogenesis and metastasis (231), unlike the AA derived EpETrE, which promote these functions (225). 18-HEPE derived from EPA via ω-hydroxylase also appears to have an anticancer role by downregulating proinflammatory and pro-proliferative factors (304), possibly via conversion to E-series resolvins. These resolvins have effects similar to the D-series resolvins, markedly reducing PMN infiltration, decreasing proinflammatory cytokines, and enhancing the resolution of inflammation (359, 401, 402).

In summary, oxylipins have important biological effects that mediate normal physiology and function. However, compared with oxylipins derived from n–3 PUFAs, those derived from n–6 PUFAs have more inflammatory, vasoconstrictory, and proliferative effects, with the exception of several examples, such as some prostanoids and/or their metabolites, lipoxins, some oxylipins from DGLA and LA, EpETrE, and some CYP-derived HETEs. But most oxylipins derived from n–3 PUFAs tend to have less activity or be anti-inflammatory, proresolving, vasodilatory, and antiproliferative. In addition, some of the anti-inflammatory and vasodilatory CYP oxylipins derived from EPA and DHA have even greater potency than their AA counterparts.

Future Developments in Nutrition and Oxylipin Research

Given the vastly differing and often opposing functions, it is critical that comprehensive analyses of the oxylipin profile be performed in order to gain an overall understanding of the biological effects. To date, few studies have examined the whole range of PUFA-derived oxylipins, but the recent development of MS-based methods is enabling this possibility (403). The number of oxylipins being measured by these methods continues to grow (e.g., novel protectin- and maresin-like products from both the n–3 and n–6 docosapentaenoic acid isomers) (18, 97). Recently, several reports have described the oxylipin profile in human blood (53, 404) and a small number of studies have examined the serum oxylipin profile in response to fish oil supplementation in healthy individuals (405–408), as well as in those who have asthma (409). These analyses and other studies that have increased dietary LA or ALA have revealed that the type of dietary fat significantly alters oxylipin profiles (55, 410–412). Furthermore, these studies have demonstrated that the oxylipins derived from LA and ALA make up more than one-half of the total oxylipin content measured. Despite this, much less is known about these oxylipins, and future studies characterizing concentrations, as well as determining their biological activities, will greatly increase our understanding of the effects of nutritional interventions in health and disease.

In this regard, there are some studies that have examined oxylipin activities side-by-side, such as for those derived from EPA or DHA compared with those derived from AA (see Tables 6 and 7), which generally, but not always, exhibit less activity in the former than the latter. However, comparisons of the biopotencies of most of the LA and ALA oxylipins are unknown, either to each other, or to their elongation counterparts. These comparisons and other studies that examine the relative biological activities of oxylipins are needed in order to further our understanding of the physiologic effects of the entire oxylipin profile. In addition, although some studies have compared the effects of oxylipin stereoisomers, much more knowledge in this area also is required. Differentiation between enzyme-mediated and autooxidation products and their potential effects in biology will also be facilitated by these studies.

It is important to note that tissue PUFA composition cannot be used to reliably predict the oxylipin content of tissues, despite the fact that this has routinely been done in the past literature. This was illustrated in a recent targeted lipidomic analysis of renal oxylipins in obese rats, which demonstrated that although the PUFA content generally reflected oxylipin content, there were notable discrepancies. For example, with 9-fold differences in the amounts of LA in the diets of these rats, the AA content of the renal phospholipid was the same, but the concentrations of several AA-derived oxylipins were different (55). This has important implications for the current debate surrounding the dietary recommendations for LA (413). Furthermore, this study indicated that PUFA conversion to oxylipins varies by as much as 10-fold between PUFAs, with ALA being metabolized to oxylipins at a greater rate than LA, AA, or EPA. This may be due to differences in incorporation and release of phospholipid FAs, as well as differences in conversion to metabolites, which may be less, more, or equally active. ALA also increased the concentration of oxylipins derived from EPA and DHA, although no EPA or DHA was present in the diets, demonstrating that PUFAs also may mediate some of their effects via oxylipins derived from PUFAs formed via elongation and desaturation of the shorter PUFAs (55). Hence, there is also a need for kinetic analysis of oxylipin formation and turnover [also referred to as fluxolipidomics (414, 415)], which also will improve our understanding of the physiologic effects of oxylipins in vivo. Comprehensive analyses that include the LA and ALA oxylipins in differing tissues in response to dietary interventions promises to yield significant novel information on the large numbers of these bioactive compounds.

Acknowledgments

All authors read and approved the final manuscript.

Footnotes

⁴

Abbreviations used: AA, arachidonic acid; AdA, adrenic acid; ALA, α-linolenic acid; COX, cyclooxygenase; cPLA₂, cytosolic phospholipase A₂; CYP, cytochrome P450; DGLA, dihomo-γ-linolenic acid; DiHDoHE, dihydroxy-docosahexaenoic acid; DiHETE, dihydroxy-eicosatetraenoic acid; DiHETrE, dihydroxy-eicosatrienoic acid; EpDPE, epoxy-docosapentaenoic acid; EpETE, epoxy-eicosatetraenoic acid; EpETrE, epoxy-eicosatrienoic acid; EpOME, epoxy-octadecenoic acid; FLAP, 5-lipoxygenase activating protein; GLA, γ-linolenic acid; HDoHE, hydroxy-docosahexaenoic acid; HEPE, hydroxy-eicosapentaenoic acid; HETE, hydroxy-eicosatetraenoic acid; HETrE, hydroxy-eicosatrienoic acid; HODE, hydroxy-octadecadienoic acid; HOTrE, hydroxy-octadecatrienoic acid; HpDoHE, hydroperoxy-docosahexaenoic acid; HpETE, hydroperoxy-eicosatetraenoic acid; LA, linoleic acid; LOX, lipoxygenase; oxo-ETE, oxo-eicosatetraenoic acid; PMN, polymorphonuclear leukocyte; sEH, soluble epoxide hydrolase.

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PERMALINK

Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs1,2

Melissa Gabbs

Shan Leng

Jessay G Devassy

Md Monirujjaman

Harold M Aukema

Abstract

Introduction

Oxylipin Formation

Cyclooxygenase

Lipoxygenase

Cytochrome P450

PUFA Substrates for Oxylipin Formation

N–6 PUFAs

Arachidonic acid.

FIGURE 1.

Linoleic acid.

FIGURE 2.

γ-Linolenic acid.

Dihomo-γ-linolenic acid.

FIGURE 3.

Adrenic acid.

FIGURE 4.

n–3 PUFAs

α-Linolenic acid.

FIGURE 5.

Stearidonic acid.

Eicosapentaenoic acid.

FIGURE 6.

Docosahexaenoic acid.

FIGURE 7.

Oxylipin Functions

TABLE 1.

TABLE 7.

n–6 PUFA oxylipin functions

COX oxylipins.

TABLE 3.

TABLE 4.

LOX oxylipins.

TABLE 2.

CYP oxylipins.

n–3 PUFA oxylipin functions

COX oxylipins.

TABLE 6.

LOX oxylipins.

TABLE 5.

CYP oxylipins.

Future Developments in Nutrition and Oxylipin Research

Acknowledgments

Footnotes

References

ACTIONS

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Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs^¹^,^²