BioMed Research International

BioMed Research International / 2015 / Article

Review Article | Open Access

Volume 2015 |Article ID 690692 |

Jarosław Szefel, Wiesław Janusz Kruszewski, Ewa Sobczak, "Factors Influencing the Eicosanoids Synthesis In Vivo", BioMed Research International, vol. 2015, Article ID 690692, 6 pages, 2015.

Factors Influencing the Eicosanoids Synthesis In Vivo

Academic Editor: Beverly Muhlhausler
Received19 Nov 2014
Accepted24 Feb 2015
Published11 Mar 2015


External factors activate a sequence of reactions involving the reception, transduction, and transmission of signals to effector cells. There are two main phases of the body’s reaction to harmful factors: the first aims to neutralize the harmful factor, while in the second the inflammatory process is reduced in size and resolved. Secondary messengers such as eicosanoids are active in both phases. The discovery of lipoxins and epi-lipoxins demonstrated that not all arachidonic acid (AA) derivatives have proinflammatory activity. It was also revealed that metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) such as resolvins, protectins, and maresins also take part in the resolution of inflammation. Knowledge of the above properties has stimulated several clinical trials on the influence of EPA and DHA supplementation on various diseases. However, the equivocal results of those trials prevent the formulation of guidelines on EPA and DHA supplementation. Prescription drugs are among the substances with the strongest influence on the profile and quantity of the synthesized eicosanoids. The lack of knowledge about their influence on the conversion of EPA and DHA into eicosanoids may lead to erroneous conclusions from clinical trials.

1. Stages of Eicosanoid Synthesis

Because the human body lacks the set of enzymes needed to synthesize the polyunsaturated fatty acids (PUFAs) and α-linolenic (ALA) and linoleic acids (LA), diet is their only source. The rate of (PUFAs) conversion into AA, DHA, and EPA is slow due to the low activity of the Δ6 desaturase. That is why only 0,2–2% of the dietary ALA is converted into EPA and DHA, while the rest undergoes β-oxidation [1]. The simplest way to bypass this step towards eicosanoid synthesis is to increase the dietary intake of DHA and EPA. Cells also use PUFAs to de novo synthesize glycerophospholipids via the Kennedy pathway or via lysophospholipids remodeling in the Lands cycle [1, 2]. Glycerophospholipids are part of the cell membranes and influence their properties and functions. The next step in eicosanoid synthesis is catalyzed by the phospholipase A2 (PLA2) with calcium ions and ATP as cofactors and involves the hydrolysis at the sn-2 position of glycerophospholipids. The products of this reaction are free fatty acids and lysophospholipids. The AA, DHA, and EPA released by this reaction are converted into biologically active eicosanoids by the 5-, 12-, and 15-lipoxygenase (LOX), cyclooxygenase (COX) -1 and -2, and other enzymes (Figure 1).

Each step of the described reactions in Figure 1 is susceptible to the activity of drugs and other factors that influence the profile and quantity of the synthesized eicosanoids. The vast body of knowledge about the drug interactions with metabolic pathways is beyond the scope of daily medical practice; however it should be taken into account when planning clinical trials. The daily clinical experience with common medication such as nonsteroidal anti-inflammatory drugs (NSAIDs) or the corticosteroids and 5-LOX inhibitors demonstrates the scope of changes in medical practice caused by drugs. For that reason, the precise determination of patient exclusion criteria is just as important in clinical trial design as the criteria of inclusion. It should be noted that, when analyzing the influence of DHA and EPA supplementation on the inflammatory markers, we will obtain very different results among patients who are prescribed medication for asthma, coronary artery disease, and diabetes and those who are taking no medications.

2. Absorption of LCPUFAs in the Gastrointestinal Tract

Triglycerides (TGs) are emulsified in the stomach and duodenum by the bile and pancreatic juices and then hydrolyzed by the pancreatic lipase into free fatty acids (FFAs) and monoacylglycerols. The FFAs absorption ratio decreases proportionally to the increasing FFA carbon chain length and hydrophobicity, whereas the ratio increases proportionally to the increasing desaturation [3]. A small part of short-chain fatty acids (SCFAs) diffuse via the intestinal mucosal membrane via the flip-flop mechanism [4]. The rest of SCFAs and all of long-chain FAs (LCFAs) are bound to the lipid raft proteins found in the cell membrane domains and transmitted through the intestinal wall [5]. The FAs absorbed by the enterocytes bind to caveolin-1 and accumulate in the cytoplasmic lipid droplets.

Before exiting the enterocytes, the PUFAs are bound into TGs at the sn-2 position [6]. Chylomicrons resulting from the bonding of TG with cholesterol, phospholipids, and apolipoproteins enter the portal circulation. Several proteins are known to transport FA across cell membranes and their distribution is specific to the tissue type and function. For example, the fatty acid translocase (FAT)/CD 36 has the highest expression in muscle tissue, whereas the enterocytes of the small intestine have the highest activity of fatty acid transport protein 4 (FATP4) which specifically binds PUFAs [7, 8].

A reduction of PUFA absorption from the intestinal lumen is observed in diseases involving the damage to the intestinal mucosa or the reduction of pancreatic lipase and bile acid secretion, such as inflammatory bowel diseases, pancreatitis, liver diseases, intestinal fistulas, and extensive resections of the small intestine. At this moment it is difficult to assess the degree to which the above-mentioned diseases influence the PUFA absorption and eicosanoid synthesis.

3. The Influence of PUFA Supply Route on the Rate of LCPUFA and Eicosanoid Synthesis

The main PUFAs substrates for this process are the dietary α-linolenic and linoleic acids. Their absorption rate is largely dependent on supply route and physical structure. Thus, the PUFA n-3/n-6 concentration ratio in cell membranes significantly increases after just 48 hours after intravenous administration, whereas after oral administration the concentration increases more slowly due to extra time needed for its absorption in the gastrointestinal tract. The profile of synthesized eicosanoids in tissues generally results from the Δ6 desaturase’s greater affinity for α-linolenic acid than for linoleic acid [9, 10]. Currently, the typical Western diet has n-6/n-3 ratio of 15 : 1, instead of the recommended 3 : 1 [11]. Raatz et al. demonstrated that the n-3 PUFAs absorbtion in the form of lipid emulsion intravenously is faster than oral fish oil capsules [12]. FA emulsification and absorption are impaired in pancreatic insufficiency, inflammatory bowel diseases, postgastrectomy states, intestinal fistulas, and extensive bowel resections [13, 14].

4. Transcellular Biosynthesis of Eicosanoids

Although eicosanoids can theoretically be synthesized in one cell, it is observed that in vivo this process occurs sequentially in different cell types, for example, blood, endothelial, and connective tissue cells [15, 16]. The intermediate from LCPUFA (e.g., PGH2 or leukotriene A4) from a single donor cell is transported to an acceptor cell which synthesizes the final product [17, 18]. To this date it has not been explained why this process occurs—after all each cell contains a full set of enzymes needed to complete the synthesis. It is even more surprising because the lipophilicity of these products makes their transport across membranes more difficult [19, 20].

Besides the change in cell number, another factor affecting the eicosanoid synthesis is the maturity of cells. In states of intense catabolism, severe infection, and sepsis and in neoplastic disease the bone marrow releases myeloid-derived suppressor cells (MDSCs). The MDSCs can be subdivided into two major groups: immature granulocytes MDSC (G-MDSC) and monocytes MDSC (M-MDSC) released from the bone marrow into the peripheral bloodstream. In order to suppress immune function, the G-MDSCs primarily use reactive oxygen species (ROS), whereas the M-MDSCs use nitric oxide synthase (iNOS) and arginase [2124]. The intensity of MDSC-induced immunosuppression dynamically changes with the patient’s state. The activity of MDSC leads to arginine starvation, lowering of the proliferation rate, and loss of the T-cell-receptor- (TCR-) associated CD3 ζ chain [25, 26]. Besides the arginine starvation in tissues, immunosuppression may be triggered by glutamine deficiency. A deficiency of these amino acids can be expected in undernourished or septic patients as well as during intense catabolic states, for example, after large surgical procedures or posttrauma [27]. The assessment of PUFA supplementation’s influence on the inflammatory reaction may be complicated by the immaturity of the immune system cells or amino acid deficiency [28, 29].

5. Factors Inhibiting the Δ6 Desaturase Activity

Δ6 desaturase catalyzes the conversion of LA and ALA into AA, EPA, and DHA. Several studies on animal models made in the 90s of the last century, mainly on rats, demonstrated that this conversion is greater in females [30, 31] and decreases due to age [3234], metabolic syndrome, diabetes [35, 36], and deficiencies of folic acid, zinc [37, 38], and vitamins B6, B12 [39, 40], and A [41]. In addition, Δ6 desaturase activity is decreased by alcohol [42]. The above-mentioned factors may significantly alter the results of clinical trials on the role of eicosanoids in the inflammatory reaction.

6. Factors Modifying the Activity of Phospholipase A2 (PLA2)

A very important step in eicosanoid synthesis is the hydrolysis of the membrane glycerophospholipids at the n-2 position by PLA2 into free PUFAs and lysophospholipids. The efficiency of this reaction determines the rate of eicosanoid synthesis. Many factors such as thrombin, angiotensin II, and interleukin-2 influence the activity of PLA2 [4345]. It is decreased in neoplasms associated with the human epidermal growth factor (HER2) overexpression as well as under the influence of angiotensin II receptor inhibitors, used in the treatment of arterial hypertension, and thrombin inhibitors commonly used in the treatment and prevention of the venous thromboembolic disease [4648]. Glucocorticoids increase the synthesis of lipocortin and annexin, strong inhibitors of PLA2 activity, leading to the inhibition of eicosanoid synthesis [4952].

The glycerophospholipid deacylation/reacylation cycle known as the Lands cycle is responsible for the continuous change of cell membrane composition and properties [53]. After the PLA2-catalyzed deacylation of phospholipids, the lysophospholipid acyltransferases (LPAATs) catalyze the reacylation of lysophospholipids [54, 55]. The efficiency of reacylation of lysophospholipids is influenced primarily by the availability of active PUFA (PUFA-CoA) and the free L-carnitine concentration, which by binding a significant amount of PUFA limits the rate of this step of eicosanoid synthesis [56, 57].

7. Factors Influencing COX Activity

NSAIDs inhibit eicosanoid synthesis by acting on COX-1 and -2. Aspirin differs from the other NSAIDs due to its ability to irreversibly acetylate COX-2 and switch this enzyme to instead generate 15R-HETE, a substrate for the 5-LOX. This results in the synthesis of 15-epi-lipoxin A4, also known as aspirin-triggered lipoxin (ATL) [58]. Celecoxib and rofecoxib inhibit the activity of acetylated COX-2 and the synthesis of the anti-inflammatory 15(R)-epi-LXA4; therefore combining them with aspirin significantly increases the risk of gastric mucosa damage [59]. These adverse interactions have not been observed after the administration of celecoxib and rofecoxib with the new acetylsalicylic acid derivative NCX 4016 [60]. The acetylated COX-2 converts EPA into 18(R)-hydroxyeicosapentaenoic acid (18R-HEPE) which is then converted by 5-LOX into resolvin (Rv) E1 and RvE2. RvE1 exerts its anti-inflammatory activity after binding with the ChemR23 and leukotriene BLT1 receptors [61, 62]. The synthesis of D-series Rv may take place via two pathways. The first of them is dependent on the aspirin-acetylated COX-2 and uses DHA as a substrate for 17(R)-hydroxy-DHA which later is converted by LOX to 17(R)-RvD1 to D4, known as the aspirin-triggered RvD-series (AT-RvDs) [63, 64], whereas the second pathway is independent of aspirin and yields resolvins similar to those from the first pathway.

Although statins use a slightly different mechanism than aspirin to modify COX-2 activity, both drugs produce 15(R) HETE which is converted by the 5-LOX to 15(R)-epi-LXA4 [65, 66]. Clinical studies of the DHA’s and EPA’s effect on the inflammatory reaction need to consider the fact that aspirin, NSAIDs, and statins all significantly change the eicosanoid profile (Equation (1)) [67].

Aspirin- (ASA-) induced acetylation of cyclooxygenase-2 (COX-2) alters enzyme’s specificity as follows:Aspirin- (ASA-) induced acetylation of cyclooxygenase-2 (COX-2) alters the enzyme specificity changing the outcome of the catalytic reaction with fatty acids leading to the so-called “aspirin-triggered (AT)” products instead. Arachidonic acid (AA) gets converted into 15R hydroxyeicosatetraenoic acid (15R-HETE), which in the presence of 5-LOX transforms further into 15-epi-lipoxins (15-epiLX) known as ATLXA4 and ATLXB4. Docosahexaenoic acid (DHA) produces aspirin-triggered resolvins and protectin D, ATRvD1 to ATRvD4 and ATPD, while reaction with eicosapentaenoic acid (EPA) results in resolvins E, ATRvE1 and ATRvE2. However certain NSAIDs can block these reactions.

8. Factors Influencing the 5-, 12-, and 15-LOX Activity

Leukotrienes (LTs) generated by 5-LOX play a key role in the pathogenesis of asthma, allergic rhinitis, and other diseases [68]. Inhibitors of this enzyme and the cysteinyl leukotriene receptor antagonists (e.g., zafirlukast, montelukast, pabilukast, and pranlukast) are successfully used to prevent the exacerbations of those diseases. The 5-LOX inhibitors are not useful in the treatment of asthmatic attacks because the inhibition of LT synthesis also inhibits the transcellular synthesis of the proresolving substances such as resolvins, protectins, and maresins [69]. Pergola et al. demonstrated that the low levels of testosterone in women are the reason for their nearly double higher level of 5-LOX products than in men [70, 71]. This observation explains why the treatment and asthma symptoms control are more difficult in women than in men.

9. Conclusions

Laboratory research on PUFAs metabolism is devoid of the confounding factors that exist in clinical practice: age, sex, social conditions, coexisting diseases, and current medication. All of the above factors change the course of numerous chemical reactions and metabolic pathways. We suggest that one of the reasons for the inconsistencies between the results of laboratory and clinical research might be imprecise patient inclusion and exclusion criteria. In this paper we presented information that is infrequently described in medical literature: some of the factors modulating the eicosanoid synthesis and the resultant inflammatory reaction. We hope that this information will help reduce the flaws at the study design stage of clinical trials regarding the PUFA supplementation.

Conflict of Interests

The authors declare that they have no competing interests.

Authors’ Contribution

Each author has participated sufficiently, intellectually or practically, in the work to take public responsibility for the content of the paper.


  1. F. Gibellini and T. K. Smith, “The Kennedy pathway-de novo synthesis of phosphatidylethanolamine and phosphatidylcholine,” IUBMB Life, vol. 62, no. 6, pp. 414–428, 2010. View at: Publisher Site | Google Scholar
  2. K. D. Ha, B. A. Clarke, and W. J. Brown, “Regulation of the Golgi complex by phospholipid remodeling enzymes,” Biochimica et Biophysica Acta, vol. 1821, no. 8, pp. 1078–1088, 2012. View at: Publisher Site | Google Scholar
  3. R. L. McKimmie, L. Easter, and R. B. Weinberg, “Acyl chain length, saturation, and hydrophobicity modulate the efficiency of dietary fatty acid absorption in adult humans,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 305, no. 9, pp. G620–G627, 2013. View at: Publisher Site | Google Scholar
  4. A. N. Carley and A. M. Kleinfeld, “Flip-flop is the rate-limiting step for transport of free fatty acids across lipid vesicle membranes,” Biochemistry, vol. 48, no. 43, pp. 10437–10445, 2009. View at: Publisher Site | Google Scholar
  5. S. Siddiqi, A. Sheth, F. Patel, M. Barnes, and C. M. Mansbach II, “Intestinal caveolin-1 is important for dietary fatty acid absorption,” Biochimica et Biophysica Acta, vol. 1831, no. 8, pp. 1311–1321, 2013. View at: Publisher Site | Google Scholar
  6. H. Mu and C.-E. Høy, “The digestion of dietary triacylglycerols,” Progress in Lipid Research, vol. 43, no. 2, pp. 105–133, 2004. View at: Publisher Site | Google Scholar
  7. J. Shim, C. L. Moulson, E. P. Newberry et al., “Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice,” Journal of Lipid Research, vol. 50, no. 3, pp. 491–500, 2009. View at: Publisher Site | Google Scholar
  8. C. Aguer, M. Foretz, L. Lantier et al., “Increased FAT/CD36 cycling and lipid accumulation in myotubes derived from obese type 2 diabetic patients,” PLoS ONE, vol. 6, no. 12, Article ID e28981, 2011. View at: Publisher Site | Google Scholar
  9. R. Portolesi, B. C. Powell, and R. A. Gibson, “Competition between 24:5n-3 and ALA for Δ 6 desaturase may limit the accumulation of DHA in HepG2 cell membranes,” Journal of Lipid Research, vol. 48, no. 7, pp. 1592–1598, 2007. View at: Publisher Site | Google Scholar
  10. R. A. Gibson, B. Muhlhausler, and M. Makrides, “Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life,” Maternal and Child Nutrition, vol. 7, supplement 2, pp. 17–26, 2011. View at: Publisher Site | Google Scholar
  11. A. P. Simopoulos, “Omega-3 fatty acids in health and disease and in growth and development,” The American Journal of Clinical Nutrition, vol. 54, no. 3, pp. 438–463, 1991. View at: Google Scholar
  12. S. K. Raatz, J. B. Redmon, N. Wimmergren, J. V. Donadio, and D. M. Bibus, “Enhanced absorption of n-3 fatty acids from emulsified compared with encapsulated fish oil,” Journal of the American Dietetic Association, vol. 109, no. 6, pp. 1076–1081, 2009. View at: Publisher Site | Google Scholar
  13. I. Kalvaria and J. E. Clain, “Diabetic diarrhoea and steatorrhoea. A case report and review of the literature,” South African Medical Journal, vol. 55, no. 14, pp. 562–564, 1979. View at: Google Scholar
  14. B. Walther, C. Clementsson, S. Vallgren, I. Ihse, and B. Akesson, “Fat malabsorption in patients before and after total gastrectomy, studied by the triolein breath test,” Scandinavian Journal of Gastroenterology, vol. 24, no. 3, pp. 309–314, 1989. View at: Publisher Site | Google Scholar
  15. S. Moncada, A. G. Herman, E. A. Higgs, and J. R. Vane, “Differential formation of prostacyclin (PGX or PGI2) by layers of the arterial wall. An explanation for the anti-thrombotic properties of vascular endothelium,” Thrombosis Research, vol. 11, no. 3, pp. 323–344, 1977. View at: Publisher Site | Google Scholar
  16. A. J. Marcus, B. B. Weksler, and E. A. Jaffe, “Enzymatic conversion of prostaglandin endoperoxide H2 and arachidonic acid to prostacyclin by cultured human endothelial cells,” The Journal of Biological Chemistry, vol. 253, no. 20, pp. 7138–7141, 1978. View at: Google Scholar
  17. S. Bunting, R. Gryglewski, S. Moncada, and J. R. Vane, “Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation,” Prostaglandins, vol. 12, no. 6, pp. 897–913, 1976. View at: Google Scholar
  18. J. Nowak and G. A. FitzGerald, “Redirection of prostaglandin endoperoxide metabolism at the platelet-vascular interface in man,” Journal of Clinical Investigation, vol. 83, no. 2, pp. 380–385, 1989. View at: Publisher Site | Google Scholar
  19. J. E. McGee and F. A. Fitzpatrick, “Erythrocyte-neutrophil interactions: Formation of leukotriene B4 by transcellular biosynthesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 5, pp. 1349–1353, 1986. View at: Publisher Site | Google Scholar
  20. N. Maugeri, V. Evangelista, A. Celardo et al., “Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis,” Thrombosis and Haemostasis, vol. 72, no. 3, pp. 450–456, 1994. View at: Google Scholar
  21. E. Peranzoni, S. Zilio, I. Marigo et al., “Myeloid-derived suppressor cell heterogeneity and subset definition,” Current Opinion in Immunology, vol. 22, no. 2, pp. 238–244, 2010. View at: Publisher Site | Google Scholar
  22. E. Ribechini, V. Greifenberg, S. Sandwick, and M. B. Lutz, “Subsets, expansion and activation of myeloid-derived suppressor cells,” Medical Microbiology and Immunology, vol. 199, no. 3, pp. 273–281, 2010. View at: Publisher Site | Google Scholar
  23. P. Raber, A. C. Ochoa, and P. C. Rodríguez, “Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives,” Immunological Investigations, vol. 41, no. 6-7, pp. 614–634, 2012. View at: Publisher Site | Google Scholar
  24. P. J. Popovic, H. J. Zeh III, and J. B. Ochoa, “Arginine and immunity,” Journal of Nutrition, vol. 137, supplement 2, no. 6, pp. 1681S–1686S, 2007. View at: Google Scholar
  25. M. Munder, H. Schneider, C. Luckner et al., “Suppression of T-cell functions by human granulocyte arginase,” Blood, vol. 108, no. 5, pp. 1627–1634, 2006. View at: Publisher Site | Google Scholar
  26. P. C. Rodriguez, A. H. Zea, J. DeSalvo et al., “L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes,” Journal of Immunology, vol. 171, no. 3, pp. 1232–1239, 2003. View at: Publisher Site | Google Scholar
  27. S. S. Yarandi, V. M. Zhao, G. Hebbar, and T. R. Ziegler, “Amino acid composition in parenteral nutrition: what is the evidence?” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 14, no. 1, pp. 75–82, 2011. View at: Publisher Site | Google Scholar
  28. P. Yaqoob and P. C. Calder, “Cytokine production by human peripheral blood mononuclear cells: differential sensitivity to glutamine availability,” Cytokine, vol. 10, no. 10, pp. 790–794, 1998. View at: Publisher Site | Google Scholar
  29. C. Murphy and P. Newsholme, “Macrophage-mediated lysis of a beta-cell line, tumour necrosis factor-alpha release from bacillus Calmette-Guerin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism,” Clinical Science, vol. 96, no. 1, pp. 89–97, 1999. View at: Publisher Site | Google Scholar
  30. S. Sfar, F. Laporte, H. Braham, A. Jawed, S. Amor, and A. Kerkeni, “Influence of dietary habits, age and gender on plasma fatty acids levels in a population of healthy Tunisian subjects,” Experimental Gerontology, vol. 45, no. 9, pp. 719–725, 2010. View at: Publisher Site | Google Scholar
  31. Y. Kawashimia, N. Uy-Yu, and H. Kozuka, “Sex-related differences in the enhancing effects of perfluoro-octanoic acid on stearoyl-CoA desaturase and its influence on the acyl composition of phospholipid in rat liver. Comparison with clofibric acid and tiadenol,” Biochemical Journal, vol. 263, no. 3, pp. 897–904, 1989. View at: Google Scholar
  32. D. F. Horrobin, “Loss of delta-6-desaturase activity as a key factor in aging,” Medical Hypotheses, vol. 7, no. 9, pp. 1211–1220, 1981. View at: Publisher Site | Google Scholar
  33. S. Hrelia, A. Bordoni, M. Celadon, E. Turchetto, P. L. Biagi, and C. A. Rossi, “Age-related changes in linoleate and α-linolenate desaturation by rat liver microsomes,” Biochemical and Biophysical Research Communications, vol. 163, no. 1, pp. 348–355, 1989. View at: Publisher Site | Google Scholar
  34. S. Hrelia, M. Celadon, C. A. Rossi, P. L. Biagi, and A. Bordoni, “Delta-6-desaturation of linoleic and α-linolenic acids in aged rats: a kinetic analysis,” Biochemistry International, vol. 22, no. 4, pp. 659–667, 1990. View at: Publisher Site | Google Scholar
  35. D. E. Barre, “The role of consumption of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids in human metabolic syndrome and type 2 diabetes—a mini-review,” Journal of Oleo Science, vol. 56, no. 7, pp. 319–325, 2007. View at: Publisher Site | Google Scholar
  36. J. Kröger and M. B. Schulze, “Recent insights into the relation of Δ5 desaturase and Δ6 desaturase activity to the development of type 2 diabetes,” Current Opinion in Lipidology, vol. 23, no. 1, pp. 4–10, 2012. View at: Publisher Site | Google Scholar
  37. K. Eder and M. Kirchgessner, “Activities of liver microsomal fatty acid desaturases in zinc-deficient rats force-fed diets with a coconut oil/safflower oil mixture of linseed oil,” Biological Trace Element Research, vol. 48, no. 3, pp. 215–229, 1995. View at: Publisher Site | Google Scholar
  38. K. Eder and M. Kirchgessner, “Zinc deficiency and the desaturation of linoleic acid in rats force-fed fat-free diets,” Biological Trace Element Research, vol. 54, no. 2, pp. 173–181, 1996. View at: Publisher Site | Google Scholar
  39. A. Bordoni, S. Hrelia, A. Lorenzini et al., “Dual influence of aging and vitamin B6 deficiency on delta-6-desaturation of essential fatty acids in rat liver microsomes,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 58, no. 6, pp. 417–420, 1998. View at: Publisher Site | Google Scholar
  40. H. Tsuge, N. Hotta, and T. Hayakawa, “Effects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolism,” Journal of Nutrition, vol. 130, no. 25, supplement, pp. 333S–334S, 2000. View at: Google Scholar
  41. R. Zolfaghari, C. J. Cifelli, M. D. Banta, and A. C. Ross, “Fatty acid Δ5-Desaturase mRNA is regulated by dietary vitamin A and exogenous retinoic acid in liver of adult rats,” Archives of Biochemistry and Biophysics, vol. 391, no. 1, pp. 8–15, 2001. View at: Publisher Site | Google Scholar
  42. U. N. Das, “Fetal alcohol syndrome and essential fatty acids,” PLoS Medicine, vol. 3, no. 5, article e247, 2006. View at: Publisher Site | Google Scholar
  43. R. N. Puri, “Phospholipase A2: its role in ADP- and thrombin-induced platelet activation mechanisms,” The International Journal of Biochemistry & Cell Biology, vol. 30, no. 10, pp. 1107–1122, 1998. View at: Publisher Site | Google Scholar
  44. S. A.-V. Leyen, M. F. Romero, M. C. Khosla, and J. G. Douglas, “Modulation of phospholipase A2 activity and sodium transport by angiotensin-(1-7),” Kidney International, vol. 44, no. 5, pp. 932–936, 1993. View at: Publisher Site | Google Scholar
  45. R. T. Abraham, M. M. McKinney, C. Forray, G. D. Shipley, and B. S. Handwerger, “Stimulation of arachidonic acid release and eicosanoid biosynthesis in an interleukin 2-dependent T cell line,” Journal of Immunopharmacology, vol. 8, no. 2, pp. 165–204, 1986. View at: Publisher Site | Google Scholar
  46. F. Caiazza, B. J. Harvey, and W. Thomas, “Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth,” Molecular Endocrinology, vol. 24, no. 5, pp. 953–968, 2010. View at: Publisher Site | Google Scholar
  47. L. Oleksowicz, Y. Liu, R. B. Bracken et al., “Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer,” Prostate, vol. 72, no. 10, pp. 1140–1149, 2012. View at: Publisher Site | Google Scholar
  48. M. Hernandez, R. Martin, M. D. Garcia-Cubillas, P. Maeso-Hernandez, and M. L. Nieto, “Secreted PLA2 induces proliferation in astrocytoma through the EGF receptor: another inflammation-cancer link,” Neuro-Oncology, vol. 12, no. 10, pp. 1014–1023, 2010. View at: Publisher Site | Google Scholar
  49. F. F. Davidson, E. A. Dennis, M. Powell, and J. R. Glenney Jr., “Inhibition of phospholipase A2 by ‘lipocortins’ and calpactins. An effect of binding to substrate phospholipids,” Journal of Biological Chemistry, vol. 262, no. 4, pp. 1698–1705, 1987. View at: Google Scholar
  50. Y. Li, H. Yamada, Y. Kita et al., “Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na+-HCO3 transport,” Journal of the American Society of Nephrology, vol. 19, no. 2, pp. 252–259, 2008. View at: Publisher Site | Google Scholar
  51. M. Holinstat, O. Boutaud, P. L. Apopa et al., “Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 2, pp. 435–442, 2011. View at: Publisher Site | Google Scholar
  52. R. M. Kramer, E. F. Roberts, J. V. Manetta, P. A. Hyslop, and J. A. Jakubowski, “Thrombin-induced phosphorylation and activation of Ca2+-sensitive cytosolic phospholipase A2 in human platelets,” Journal of Biological Chemistry, vol. 268, no. 35, pp. 26796–26804, 1993. View at: Google Scholar
  53. W. E. M. Lands, “Stories about acyl chains,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1483, no. 1, pp. 1–14, 2000. View at: Publisher Site | Google Scholar
  54. H. Shindou and T. Shimizu, “Acyl-CoA:lysophospholipid acyltransferases,” Journal of Biological Chemistry, vol. 284, no. 1, pp. 1–5, 2009. View at: Publisher Site | Google Scholar
  55. E. Soupene and F. A. Kuypers, “Mammalian long-chain acyl-CoA synthetases,” Experimental Biology and Medicine, vol. 233, no. 5, pp. 507–521, 2008. View at: Publisher Site | Google Scholar
  56. A. Arduini, V. Tyurin, Y. Tyuruna et al., “Acyl-trafficking in membrane phospholipid fatty acid turnover: the transfer of fatty acid from the acyl-L-carnitine pool to membrane phospholipids in intact human erythrocytes,” Biochemical and Biophysical Research Communications, vol. 187, no. 1, pp. 353–358, 1992. View at: Publisher Site | Google Scholar
  57. A. Arduini, G. Mancinelli, and R. R. Ramsay, “Palmitoyl-L-carnitine, a metabolic intermediate of the fatty acid incorporation pathway in erythrocyte membrane phospholipids,” Biochemical and Biophysical Research Communications, vol. 173, no. 1, pp. 212–217, 1990. View at: Publisher Site | Google Scholar
  58. C. N. Serhan, “Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution,” Prostaglandins and Other Lipid Mediators, vol. 68-69, pp. 433–455, 2002. View at: Publisher Site | Google Scholar
  59. S. Fiorucci, O. M. De Lima Jr., A. Mencarelli et al., “Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage,” Gastroenterology, vol. 123, no. 5, pp. 1598–1606, 2002. View at: Publisher Site | Google Scholar
  60. J. L. Wallace, S. R. Zamuner, W. McKnight et al., “Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 286, no. 1, pp. G76–G81, 2004. View at: Google Scholar
  61. M. Arita, T. Ohira, Y. P. Sun, S. Elangovan, N. Chiang, and C. N. Serhan, “Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation,” Journal of Immunology, vol. 178, no. 6, pp. 3912–3917, 2007. View at: Publisher Site | Google Scholar
  62. S. F. Oh, P. S. Pillai, A. Recchiuti, R. Yang, and C. N. Serhan, “Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation,” Journal of Clinical Investigation, vol. 121, no. 2, pp. 569–581, 2011. View at: Publisher Site | Google Scholar
  63. Y.-P. Sun, S. F. Oh, J. Uddin et al., “Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation,” Journal of Biological Chemistry, vol. 282, no. 13, pp. 9323–9334, 2007. View at: Publisher Site | Google Scholar
  64. S. Hong, K. Gronert, P. R. Devchand, R.-L. Moussignac, and C. N. Serhan, “Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation,” The Journal of Biological Chemistry, vol. 278, no. 17, pp. 14677–14687, 2003. View at: Publisher Site | Google Scholar
  65. H. R. O'Neal, T. Koyama, E. A. S. Koehler et al., “Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome,” Critical Care Medicine, vol. 39, no. 6, pp. 1343–1350, 2011. View at: Publisher Site | Google Scholar
  66. M. Spite and C. N. Serhan, “Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins,” Circulation Research, vol. 107, no. 10, pp. 1170–1184, 2010. View at: Publisher Site | Google Scholar
  67. J. N. Fullerton, A. J. O'Brien, and D. W. Gilroy, “Lipid mediators in immune dysfunction after severe inflammation,” Trends in Immunology, vol. 35, no. 1, pp. 12–21, 2014. View at: Publisher Site | Google Scholar
  68. T. Hammarberg, P. Provost, B. Persson, and O. Rådmark, “The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity,” The Journal of Biological Chemistry, vol. 275, no. 49, pp. 38787–38793, 2000. View at: Publisher Site | Google Scholar
  69. C. N. Serhan, S. Krishnamoorthy, A. Recchiuti, and N. Chiang, “Novel anti-inflammatory—pro-resolving mediators and their receptors,” Current Topics in Medicinal Chemistry, vol. 11, no. 6, pp. 629–647, 2011. View at: Publisher Site | Google Scholar
  70. C. Pergola, A. Rogge, G. Dodt et al., “Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes,” The FASEB Journal, vol. 25, no. 10, pp. 3377–3387, 2011. View at: Publisher Site | Google Scholar
  71. C. Pergola, G. Dodt, A. Rossi et al., “ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19881–19886, 2008. View at: Publisher Site | Google Scholar

Copyright © 2015 Jarosław Szefel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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