Elsevier

Progress in Lipid Research

Volume 53, January 2014, Pages 108-123
Progress in Lipid Research

Review
Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer

https://doi.org/10.1016/j.plipres.2013.11.003Get rights and content

Abstract

Epoxygenated fatty acids (EpFAs), which are lipid mediators produced by cytochrome P450 epoxygenases from polyunsaturated fatty acids, are important signaling molecules known to regulate various biological processes including inflammation, pain and angiogenesis. The EpFAs are further metabolized by soluble epoxide hydrolase (sEH) to form fatty acid diols which are usually less-active. Pharmacological inhibitors of sEH that stabilize endogenous EpFAs are being considered for human clinical uses. Here we review the biology of ω-3 and ω-6 EpFAs on inflammation, pain, angiogenesis and tumorigenesis.

Introduction

Arachidonic acid (ARA, 20:4ω-6) compromises a major component in the membrane phospholipids and plays a critical role in cell signaling [1], [2], [3]. Upon cellular stimulation, the incorporated ARA is released by several enzymes including diacylglycerol lipase and phospholipase A2 (PLA2) to generate free intracellular ARA, which is rapidly metabolized by a series of enzymes to generate lipid mediators (LMs) in a process collectively termed the ARA cascade [1], [2], [3]. The lipid signaling in the ARA cascade is important because the LMs regulate many fundamental biological processes from inflammation to blood flow, and therefore are important therapeutic targets for multiple human disorders [1], [2], [3]. There are three major branches in the ARA cascade: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) pathways. The COX and LOX pathways generate predominately but not exclusively pro-inflammatory LMs and a variety of approved drugs target these two branches [2]. In contrast, our knowledge of the CYP pathway, which is usually regarded as the third branch of the ARA cascade, is rather limited and has not yet been exploited therapeutically [3], [4], [5], [6]. Lipid amides and other endocannabinoids are important chemical mediators [7]. However, they are usually not considered as part of the ARA cascade and only their epoxygenated metabolites are discussed here.

The CYP branch, which was first described in 1980s, converts ARA to two major classes of LMs: CYP ω/ω-1 hydroxylases (mainly CYP4A and CYP4F) catalyze the hydroxylation of ARA to generate 19-hydroxyeicosatetraenoic acid (19-HETE) and 20-HETE [8]. In the other branch of the CYP pathway, CYP epoxygenases (mainly CYP2C and CYP2J) catalyze the epoxidation of ARA to generate epoxygenated fatty acids (EpFAs) called epoxyeicosatrienoic acids (EETs) that include four regioisomers of 5,6-, 8,9-, 11,12- and 14,15-EET [3]. 20-HETE has been shown to have an array of largely detrimental effects, inducing hypertension, endothelial dysfunction, inflammation, cardiovascular diseases, angiogenesis and tumor growth [9], [10], [11], [12], [13], [14]. EETs have been investigated as autocrine and paracrine signaling molecules which have anti-inflammatory, vasodilative, anti-hypertensive, cardio-protective, renal-protective, pro-angiogenic and analgesic effects [5]. As we simplistically discuss LMs with terms such as inflammatory or anti-inflammatory and suggest beneficial or detrimental effects, it is important to remember most LMs have multiple effects that maintain a critical balance in normal physiology. Although chemically stable (other than the 5,6-EET regioisomer), EETs are highly unstable in vivo mainly due to the rapid metabolism by soluble epoxide hydrolase (sEH, encoded by EPHX2) to the less-active fatty acid diols termed dihydroxyeicosatrienoic acids (DHETs) (Fig. 1) [6]. Therefore, blocking the degradation of generally beneficial EETs by targeting sEH is pharmacologically attractive. During the past decade, pharmacological inhibitors of sEH (sEHIs) with IC50 values in nM–pM range and good pharmacokinetic (PK) profiles in vivo have been developed [4], [15]. The sEHIs, which stabilize endogenous EETs, are promising drug candidates for multiple human diseases and have been evaluated in phase II human trials [4], [16].

Linoleic acid (18:2, ω-6), which is a biosynthetic precursor to generate ARA and is highly abundant in the western diet [17], is also a substrate of the CYP/sEH pathway [6]. The metabolism of linoleic acid by CYP epoxygenases generates the linoleic epoxides including 9,10-epoxyoctadecenoic acid (9,10-EpOME) and 12,13-epoxyoctadecenoic acid (12,13-EpOME), which are further metabolized by sEH to form the linoleic diols including 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME) and 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) [6]. EpOMEs have been associated with multiple organ failure and adult respiratory distress syndrome in some severe burn patients [18], [19], [20], [21]. We have shown that the sEH-mediated conversion of EpOMEs to DiHOMEs plays a critical role in the cellular toxicity of EpOMEs [22]. With a high consumption of linoleic acid in the western diet, it is critical to investigate the effects of linoleic acid metabolites on human health, in particular EpOMEs and DiHOMEs which have been demonstrated to have toxic effects.

Besides ω-6 polyunsaturated fatty acids (PUFAs), ω-3 PUFAs such as eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 22:6ω-3) are also substrates of the enzymes in the ARA cascade, which convert them to the ω-3-series LMs [23], [24], [25]. A major theory to explain the health-promoting effects of ω-3 PUFAs is that they compete with ARA for the enzymatic metabolism, decreasing the formation of ω-6-series LMs that are predominately pro-angiogenic and pro-inflammatory and increasing ω-3-series LMs that have less detrimental and possibly beneficial effects [23], [24], [25]. Indeed, the metabolism of ω-3 PUFAs by COX and LOX enzymes generates ω-3-series prostaglandins [26], [27] and leukotrienes [28], as well as unique ω-3 autacoids such as resolvins and protectins [25], which have anti-inflammatory or anti-angiogenic effects. EPA and DHA are believed to be poor substrates of COX and LOX enzymes [23], however they have been shown to be highly efficient alternative substrates of CYP epoxygenases, which convert them to the ω-3 EpFAs named epoxyeicosatetraenoic acids (EEQs) and epoxydocosapentaenoic acids (EDPs) respectively [29] (Fig. 2). Compared with EETs, the ω-3 EpFAs are generally better substrates of sEH which convert them to the corresponding ω-3-series fatty acid diols [30]. As expected from its structure, the 19,20-EDP is more slowly turned over by the sEH. Compared with EETs, the biological effects of the ω-3 EpFAs are less-studied. EEQs and EDPs have similar or more potent effects for vasodilation, anti-inflammation and analgesia than EETs [30], [31], while EDPs and EETs have opposite activities on angiogenesis, tumor growth and metastasis [32], [33]. This offers us additional opportunities to manipulate profiles of EpFAs to improve human health.

EpFAs have been demonstrated to be involved in many human diseases and hold promise as novel therapeutic targets [5]. This review discusses the biological activities and mechanisms of actions of the ω-6 and ω-3 EpFAs including EETs, EEQs and EDPs on inflammation, pain, angiogenesis and cancer. EpFAs have also been shown to have anti-hypertensive, cardio-protective and organ protective effects. These topics have been covered in several recent reviews [5], [34], [35] and will not be discussed here.

CYP epoxygenases catalyze epoxidation of the double bonds of ARA to generate EETs. The epoxidation can occur at all of the four double bonds of ARA, leading to formation of four regioisomers (5,6-, 8,9-, 11,12- and 14,15-EET) [3]. Among these regioisomers, 5,6-EET is chemically unstable and undergoes rapid cyclization and hydrolysis, the other isomers are chemically stable except under acidic conditions. The CYPs referred to as epoxygenases are by no means specific, for example, they also oxidize reactive methylenes in PUFAs. The biochemistry of CYP epoxygenases in EETs biosynthesis have been discussed in several reviews [3], [36], [37]. A series of CYP enzymes such as CYP1A, CYP2B, CYP2C, CYP2D, CYP2G, CYP2J, CYP2N, and CYP4A are capable of converting ARA to EETs [3]. Generally each enzyme produces EETs with different profiles of optical- and regioisomers. In mammals CYP2C and CYP2J isoforms appear to be the predominate epoxygenases. For human and rat, CYP2C isoforms are the most abundant in liver and kidney, and CYP2J are the major ones in heart [3]. CYP2C and CYP2J are also the major epoxygenases in endothelium [36]. Similar to other CYP enzymes, the expression of CYP epoxygenases can be modulated by environmental factors and cellular stimuli [3], [36], [38]. Among these, the most physiologically relevant stimulator of CYP epoxygenase expression is hypoxia [39], [40], which is a critical regulator to stimulate neovasculization [41], suggesting a role of CYP epoxygeanses in angiogenesis.

Once formed, EETs are rapidly metabolized by sEH to generate the corresponding fatty acid diols called DHETs [6]. Compared with EETs, DHETs are widely believed to be inactive or less-active [5]; a recent study shows that opposite to the anti-inflammatory effects of EETs, DHETs are pro-inflammatory in stimulating monocyte migration [42]. Therefore the sEH-mediated metabolic step is generally regarded as a loss of beneficial biological activities. The biochemistry, expression and regulation of sEH have been discussed in several reviews [4], [5], [6]. The mammalian sEH is a homodimer composed of two ∼62 KDa monomers. Each monomer has a ∼35 KDa C-terminal domain which displays epoxide hydrolase activity and a ∼25 KDa N-terminal domain which appears to have phosphatase activity [43]. sEH is highly expressed in many tissues including liver, kidney, lung, heart, brain, spleen, endothelium and mammary gland [6]. The highest sEH activity was observed in liver, followed with kidney. Even in organs with relatively low sEH activity, the enzymatic activity can be high in individual cell types. The expression of sEH is inducible by peroxisome proliferator-activated receptor α (PPARα) and PPARγ agonists [6]. PPARγ agonists have been shown to inhibit tumor growth and metastasis by blocking angiogenesis [44], [45], the anti-cancer effect of these compounds could be partially mediated by reduction of the amount of EETs via stimulation of sEH [32]. The expression of sEH is also up-regulated by angiotensin II [46] and homocysteine [47]. The sEH catalyzes hydrolysis of EpFAs by addition of water, in a two-step, base-catalyzed mechanism via the formation of a covalent intermediate [6]. Pharmacological inhibitors, many of which have a urea, amide, or carbamate group as the central pharmacophore to mimic the reaction transition states, were designed based on the catalytic mechanism of sEH enzyme [15]. A sEHI APAU has been evaluated in a Phase IIA trial targeting hypertension as the primary indication, recently more potent and metabolically stable sEHIs have been developed and are being considered for evaluation in human trials. FDA-approved anti-cancer drugs sorafenib (Nexavar®) and regorafenib (Stivarga®) are also potent sEH inhibitors with IC50 values in the low nM–pM range [48], [49].

Besides the hydrolysis catalyzed by sEH, EpFAs are also metabolized by other pathways including β-oxidation, chain shortening and chain elongation [3]. EpFAs can be re-incorporated into the membrane phospholipids by acyl transferase causing a significant proportion of EpFAs to exist as esterified forms in the membrane phospholipids. In comparison, the fatty acid diols are less readily incorporated in the membrane phospholipids [3]. The biological significance of the membrane-incorporated EpFAs remains poorly studied. To address this question, more reliable analytical methods are needed to quantify the membrane-incorporated EpFAs and diols and particularly to evaluate the kinetics of this process. EpFAs could also be further metabolized by COX, LOX and CYP enzymes to generate novel series of LMs, though little is known about the chemical structures and biological activities of these lipid metabolites. Both 5,6- and 8,9-EET have been shown to be substrates of COX enzymes, which convert them to metabolites which may have potent effects of vasodilation or stimulation of cell proliferation [50], [51], [52]. A COX metabolite of 8,9-EET, 11-hydroxy-8,9-epoxyeicosatrienoic acid, has been shown to be >1000-fold more potent than 8,9-EET in stimulating cell proliferation and c-fos expression in rat glomerular mesangial cells [52]. Previous research from our laboratory has shown that sEHIs dramatically synergize with COX or LOX inhibitors to reduce inflammation [53], [54]. It would be interesting to investigate whether the observed synergistic interactions are in part mediated by the LOX and COX-derived metabolites of EETs. It was recently shown that EPA-derived 17,18-EEQ is further metabolized to generate 12-OH-17,18-EEQ, which inhibited LTB4-induced neutrophil chemotaxis and polarization in vitro with EC50 = 0.6 nM [55]. Other pathways such as β-oxidation and chain elongation also participate in the metabolism of EETs. When sEH is inhibited, other metabolic pathways of EETs are up-regulated [56]. Since the fates of EETs are regulated by multiple metabolic pathways, pharmacological inhibition or genetic deletion of sEH only increases level of EETs in a limited range.

The ω-3 PUFAs including EPA and DHA were mainly derived from cold-water fish, and were of dramatically varying quality. Overall quality of fish oils is increasing, their composition is defined, and increasingly they may be derived from many sources including krill, tissues of marine mammals, algae and yeast. They are among the most popular dietary supplements in United States. In addition, major food companies are increasingly adding ω-3 PUFAs to food as value-added ingredients. Two ω-3 PUFA products have been approved by the FDA as prescription drugs to treat hypertriglyceridemia, including Lovaza® from GSK and Vascepa® from Amarin. Although epidemiological and pre-clinical data show a correlation between increases in ω-3 relative to ω-6 PUFAs in the diet and reduced risks of various chronic diseases such as cancers [57], [58], [59], [60], [61], [62], [63] and macular degeneration [64], [65], [66], [67], the underlying mechanisms are largely unknown. A dominant theory to explain the effects of ω-3 PUFAs is that they suppress the metabolism of ARA which generates predominately pro-inflammatory and pro-angiogenic eicosanoids, or they serve as alternative substrates to generate ω-3 LMs which have unique biological actions [24], [25], [26], [28]. Indeed, EPA effectively competes with ARA for metabolism by the COX enzymes, the COX-2 metabolite of EPA, prostaglandin E3 (PGE3), has less pro-angiogenic and pro-inflammatory effect than the ARA-derived metabolite PGE2 [26], [27]. 5-LOX plays a critical role in the anti-angiogenic effect of DHA, the 5-LOX metabolite of DHA, 4-hydroxy-docosahexaenoic acid (4-HDHA), has potent anti-angiogenic effect and genetic deletion of 5-LOX significantly attenuated the anti-angiogenic effect of DHA in a murine retinopathy model [28]. In a human study, Dwyer et al. showed that a diet rich in ω-3 PUFAs decreased the risks while a diet rich in ω-6 PUAFs increased the risks of atherosclerosis only in the sub-population with high 5-LOX activity [68]. These studies suggest that there is a strong gene-diet interaction. Understanding the molecular mechanism of ω-3 PUFAs could help to design better therapeutic paradigms and human trials to clarify their health benefits.

Besides the well studied COX and LOX pathways, recent research showed that ω-3 PUFAs are good alternative substrates of CYP epoxygenases [29]. Cell-free enzymatic assays showed that CYP epoxygenases have similar activities toward ARA, EPA and DHA [29]. CYP epoxygenases selectively catalyze the epoxidation of the terminal double bond of ω-3 PUFAs, leading to predominate formation of 17,18-EEQ from EPA and 19,20-EDP from DHA, while no such selectivity was observed for biosynthesis of EETs from ARA [29], [69], [70], [71]. Most of the ω-3 EpFAs are turned over by sEH more rapidly than EETs except for 19,20-EDP from DHA [30]. The high biosynthesis and low degradation of 19,20-EDP make it among the most abundant ω-3 EpFAs in vivo [29], [72], [73], [74]. In endothelial cells, EPA has been shown to increase transcription of CYP2J2 in a time- and dose-dependent manner resulting in increased biosynthesis of EpFAs [75].

Because several PUFAs including linoleic acid, ARA, EPA and DHA are substrates of the CYP epoxygenases, the CYP pathway generates a large number of ω-6 and ω-3 EpFAs, whose levels are further regulated by the sEH enzyme [29], [72], [73], [74]. Inhibition of sEH is thus a ‘‘shot-gun” approach, stabilizing multiple ω-3 and ω-6 EpFAs. Inhibition of sEH will stabilize EpFAs that are present in the tissue, but only will change the relative amounts of EpFAs based on the preference of the sEH for the EpFA substrates. In most tissues EETs are the major EpFAs because ARA is the most abundant PUFA in cell membrane, while DHA-derived EDPs could be the major EpFAs in DHA-rich tissues such as retina and brain [17]. In zebrafish which is DHA-rich, the most abundant EpFA is DHA-derived 19,20-EDP [76]. In mammals, the relative abundance of ω-6 ARA and ω-3 EPA and DHA in tissues are largely determined by dietary intake of PUFAs because mammals lack the enzymes for de novo biosynthesis of ω-3 PUFAs [17], [23]. Studies on man and other mammals demonstrate that ω-3 supplementation increases levels of EEQs and EDPs in plasma and tissues. A 3-week feeding of ω-3 PUFA ethyl ester in rats reduced levels of EETs and increased levels of EEQs and EDPs in plasma, brain, heart, kidney, liver and lung [29]. Supplementation of 4 g/day of ω-3 PUFA ethyl ester (465 mg EPA and 375 mg DHA per 1 g capsule) in healthy volunteers for 4 weeks induced a respective ∼5- and ∼2-fold increase of EEQs and EDPs in human plasma, while the levels of EETs were not significantly changed [72], [73]. Zivkovic et al. reported that supplementation of 4 g/d of fish oil (1.9 g/d EPA and 1.5 g/d DHA) in immunoglobulin A nephropathy patients for 24 months caused a ∼2-fold increase of DHA epoxides and diols in plasma [74].

Section snippets

EETs on inflammation

Dysregulated inflammation is a common feature of most human diseases, therefore modulation or inhibition of inflammation has been proven to be an effective therapeutic strategy [77], [78], [79]. LMs play a central role to regulate inflammation. One of the most important LMs in inflammation is PGE2 which is a COX-2 metabolite of ARA and has predominantly but not exclusively pro-inflammatory activity [80]. Aspirin has been used to inhibit inflammatory pain and fever for over a century. It

EETs on inflammatory and neuropathic pain

A potential therapeutic application for EpFAs, their mimics or sEHI is for alleviation of inflammatory and neuropathic pain. Based on a French survey, chronic pain persists within 30% of the population with 7% having characteristics of neuropathic pain [113]. The cost from this chronic pain, considering both health care costs and cost of lost productivity, is estimated to be up to 635 billion dollars for the United States [114]. Despite this expense, up to 40% of those with chronic pain say it

EETs on angiogenesis

Angiogenesis, the formation of new blood vessels from pre-existing vessels, is critical for multiple physiological and pathological processes [136]. Blocking angiogenesis is a promising strategy to treat cancers and FDA has approved multiple anti-angiogenic drugs for cancer treatment [137]. Anti-angiogenic drugs are also used to treat macular degeneration [138]. On the other hand, pro-angiogenic drugs, which stimulate neovascularization to increase blood flow to tissues, could be useful for

Biological activities of EETs on tumorigenesis in vitro

Angiogenesis is required for tumor growth and metastasis of almost all types of cancers. The pro-angiogenic effects of EETs indicate their potential roles in tumor progression. The Wang group first showed that over-expression of CYP2J2 or treatment with synthetic EETs in cancer cells stimulated cancer cell proliferation, migration and invasion [164], [165], [166]. Follow-up studies showed that EETs stimulated proliferation, migration and invasion in certain cancer cell lines. Nithipatikom et

Biological activities of ω-3 EpFAs on vascular tone and inflammation

EDPs have been shown to be the most potent EpFAs in the dilation of blood vessels [31]. EDP regioisomers (except 5,6-EDP which is chemically unstable) had EC50 values ranging from 0.5 to 24 pM for dilation of porcine coronary arterioles precontracted with endothelin, while the corresponding diol 13,14-DiHDPA was >1000-fold less active with an EC50 value of 30 ± 22 nM, and the parent fatty acid DHA only dilated vessels at ⩾1 μM. EDPs also potently activated BKca channels with a 1000-fold higher

Conclusion and future work

Multiple approaches were carried out to investigate the biological activities of EpFAs in cell cultures and animal experiments. These approaches include (1) treatment with synthetic EpFAs, (2) pharmacological inhibition of CYP epoxygenases, (3) inhibition of sEH using sEHIs with diverse structural features, (4) transgenic expression of CYP epoxygenases, and (5) transgenic over-expression or knockout of sEH. Substantial evidence obtained from these studies support that EpFAs are important

Acknowledgments

We acknowledge support from National Institute on Environmental Health Sciences R01 ES02710 and P42 ES04699, Research Investments in the Sciences and Engineering (RISE) Program of University of California Davis. B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Society.

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