Eicosatetraenoic Acid

What is Eicosatetraenoic Acid?

Eicosatetraenoic acid (ETA) refers to the family of polyunsaturated, long-chain fatty acids with a 20-carbon backbone and four double bonds. There are eight total isomers of ETA. Arachidonic acid, an omega-6 fatty acid, is the most prevalent and well-studied isomer. Though uncommon, some ETAs are essential fatty acids found in some fungi, fish oils, and human and animal fat tissue. Other ETAs, including arachidonic acid, can be synthesized by the elongation and dehydration of shorter essential fatty acids, including linoleic acid.

ETAs directly impact a variety of physiological states, and their impact is largely effected by their derivatives, which are bioactive compounds including epoxide eicosatrienoic acids (EETs), lipoxins (LXs), and hydroxyeicosatetraenoic acids (HETEs)¹. Variants of each of these molecules are associated with cancers, cardiovascular diseases, inflammation, and other conditions; and further metabolization of these compounds leads to the production of prostaglandins, leukotrienes, and other immune signaling molecules.

Eicosatetraenoic acid and inflammation

Most ETAs are proinflammatory. For example, elevated arachidonic acid levels are associated with early systemic inflammation in preterm infants and are an early indicator of nonalcoholic fatty liver disease, which is largely driven by an excessive inflammatory response². Conversely, arachidonic acid can also alleviate inflammation. One way by which it achieves this is by interfering with the activity of Toll-like receptor 4 (TLR4) in cardiomyocytes and macrophages by binding to the TLR4 coreceptor myeloid differentiation factor 2 (MD2), blocking the formation of the active TLR4–MD2 complex and downstream proinflammatory cytokine release³. Studies in rats have shown that treatment with arachidonic acid can lower inflammation4; however, it is unclear whether this response is due directly to arachidonic acid or to one of its downstream mediators.

Numerous correlations have been identified linking ETA-derived metabolites and the inflammatory response. Most derivatives of 8,11,14,17-ETA are anti-inflammatory, whereas arachidonic acid derivatives tend to be proinflammatory. Most epoxide eicosatrienoic acids (EETs) drive inflammation by promoting vasodilatation, angiogenesis, and cellular proliferation⁵; however, 11,12-EET can limit inflammation by inhibiting leukocyte recruitment. Studies have suggested that 11,12-EET might play an important role during infection-induced inflammation by counterbalancing proinflammatory signals⁶. Lipoxins, including LXA4 and LXB4, modulate inflammation by inhibiting neutrophil migration, inducing macrophage switching from a pro- to an anti-inflammatory phenotype, and stimulating efferocytosis.

ETA-derived hydroxyeicosatetraenoic acids (HETEs) can modulate inflammation bidirectionally. For example, in a mouse model of B. burgdorferi-induced Lyme disease, elevated levels of 12-HETE recruit inflammatory monocytes and anti-inflammatory macrophages during the early and late stages of infection, respectively, suggesting that 12-HETE may recruit cells to clear infection while counterbalancing proinflammatory signals from other mediators⁷. HETEs can also drive inflammation in Alzheimer’s disease. 12-HETE and 15-HETE are both elevated in the temporal and frontal lobes of Alzheimer’s disease patients, and some of these patients display elevated 12-HETE levels in the cerebrospinal fluid.

Eicosatetraenoic acid and cardiovascular disease

ETA levels are linked to many cardiovascular diseases. For example, low circulating levels of ETA are associated with increased severity and mortality in individuals with chronic heart failure, and plasma arachidonic acid levels positively correlate with atherosclerotic cardiovascular diseases, venous thromboembolism, and ischemic heart disease. Although further studies are needed, these data suggest that ETA may serve as a biomarker for diverse cardiovascular diseases⁸.

ETA-derived metabolites also impact the severity of cardiovascular disease. For example, both EETs and HETEs regulate vascular endothelial and smooth muscle cells to mediate blood vessel contractility, and abnormally low EET and HETE levels may lead to vascular disorders such as hypertension. Some studies have shown that increasing EET levels can improve vascular function and sodium excretion and reduce inflammation. Similarly, the ETA-derivative LXA4 plays a protective role during myocardial ischemia⁹. Further studies exploring the ETA metabolic pathways are needed and may lead to new targets for cardiovascular disease treatment.

Eicosatetraenoic acid and cancer

Arachidonic acid and many of its downstream metabolites promote tumor development by regulating cellular carcinogenesis, tumor cell proliferation, chemotaxis, migration, and apoptosis. Exposure to arachidonic acid can drive tumor cells to adopt an abnormal cellular shape, improving cell motility and increasing the rate of metastasis. Furthermore, during both ovarian and breast cancer, this ETA isomer limits immune cell killing of tumor cells, likely by disrupting lipid rafts within immune cells. Studies have shown that breast cancer patients with higher concentrations of arachidonic acid displayed reduced intratumoral T cells and activated natural killer cells, both of which are crucial for tumor control¹⁰.

Dysregulation of arachidonic acid metabolism can further impact cancer development. For example, single nucleotide polymorphisms in arachidonic acid catabolic pathways have been linked with susceptibility to prostate cancer and several studies in animal models have investigated whether inhibiting catabolism of arachidonic into 20-HETE could improve cancer outcomes, demonstrating marked reduction in tumor size in animals. However, further studies are needed to examine whether 20-HETE inhibition is a viable cancer therapeutic for humans¹¹.

Several ETA derivatives, including lipoxins, also mediate anti-carcinogenic effects through a variety of mechanisms. For example, oral administration of an LXA4 biomimetic analogue reduced splenic and intratumoral neutrophils and myeloid-derived suppressor cell populations, stimulated tumor T cell recruitment, and inhibited tumor growth in a mouse model of colorectal cancer¹². More research as well as clinical studies are needed, however, to determine whether LXA4 could be a viable cancer treatment.

Eicosatetraenoic acid and reproduction

Diverse stages of reproduction are impacted by ETAs. For example, arachidonic acid catabolism is required for oocyte maturation and accurate DNA methylation in embryos. When elevated in oocyte follicular fluid, arachidonic causes oxidative stress and induces the expression of growth/differentiation factor-15, which can suppress osteoblast differentiation and new bone development in the developing embryo¹³. Male fertility is also impacted by ETAs. Sperm exposure to arachidonic acid can lead to DNA damage and reduced sperm motility, and elevated levels of this metabolite in testes correlate with high numbers of defective sperm¹⁴.

Eicosatetraenoic acid and skin

As the second most abundant polyunsaturated essential fatty acid in the skin, arachidonic acid plays several important roles, including the acceleration of wound healing by promoting mesenchymal stem cell migration. The ETA derivative 12-HETE also contributes to the healing process by inducing chemotaxis of keratinocyte and epidermal Langerhans cells. However, 12-HETE can also drive carcinogenesis and is elevated in sun-exposed skin compared to normal skin¹⁵.

Lipoxin A4, on the other hand, can protect against sun damage. Topical pretreatment of LXA4 reduced ultraviolet radiation-induced skin edema, neutrophil recruitment, MMP-9 activity, collagen thickening, and epidermal thickening, suggesting that LXA4 could be a viable treatment option for skin conditions such as wounds and burns¹⁶.

Eicosatetraenoic acid and research

As of May 2024, there are over 7,000 collective citations for eicosatetraenoic acid and arachidonic acid in research publications (excluding books and documents) on Pubmed. As researchers continue to unravel the pharmacological and physiological mechanisms of ETA and its derivatives, more research, both in vitro and in vivo, is required to assess its potential use for the treatment of various cancers as well as cardiovascular, fertility, and inflammatory disorders.

References

1. National Library of Medicine, National Center for Biotechnology Information. PubChem Compound Summary, Arachidonic Acid (CID 444899). https://pubchem.ncbi.nlm.nih.gov/compound/Arachidonic-Acid
2. Sztolsztener K, Chabowski A, Harasim-Symbor E, et al. Arachidonic Acid as an Early Indicator of Inflammation during Non-Alcoholic Fatty Liver Disease Development. Biomolecules. 2020;10(8):1-15. doi:10.3390/BIOM10081133
3. Zhang Y, Chen H, Zhang W, et al. Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5). doi:10.1016/J.BBADIS.2020.165683
4. Gundala NKV, Das UN. Arachidonic acid-rich ARASCO oil has anti-inflammatory and antidiabetic actions against streptozotocin + high fat diet induced diabetes mellitus in Wistar rats. Nutrition. 2019;66:203-218. doi:10.1016/J.NUT.2019.05.007
5. Michaelis UR, Fleming I. From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: Epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther. 2006;111(3):584-595. doi:10.1016/J.PHARMTHERA.2005.11.003
6. Liu Y, Zhang Y, Schmelzer K, et al. The antiinflammatory effect of laminar flow: the role of PPARgamma, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc Natl Acad Sci U S A. 2005;102(46):16747-16752. doi:10.1073/PNAS.0508081102
7. Blaho VA, Buczynski MW, Brown CR, et al. Lipidomic analysis of dynamic eicosanoid responses during the induction and resolution of Lyme arthritis. J Biol Chem. 2009;284(32):21599-21612. doi:10.1074/JBC.M109.003822
8. Zhang T, Zhao J, Schooling CM. The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study. EBioMedicine. 2021;63. doi:10.1016/j.ebiom.2020.103189
9. Agostinucci K, Hutcheson R, Hossain S, et al. Blockade of 20-hydroxyeicosatetraenoic acid receptor lowers blood pressure and alters vascular function in mice with smooth muscle-specific overexpression of CYP4A12-20-HETE synthase. J Hypertens. 2022;40(3):498-511. doi:10.1097/HJH.0000000000003038
10. Hammoud MK, Dietze R, Pesek J, et al. Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK-STAT signaling in macrophages by perturbing lipid raft structures. Mol Oncol. 2022;16(17):3146-3166. doi:10.1002/1878-0261.13221
11. Amirian ES, Ittmann MM, Scheurer ME. Associations between arachidonic acid metabolism gene polymorphisms and prostate cancer risk. Prostate. 2011;71(13):1382-1389. doi:10.1002/PROS.21354
12. Dong T, Dave P, Yoo EJ, et al. NAP1051, a Lipoxin A4 Biomimetic Analogue, Demonstrates Antitumor Activity Against the Tumor Microenvironment. Mol Cancer Ther. 2021;20(12):2384-2397. doi:10.1158/1535-7163.MCT-21-0414
13. Ma Y, Zheng L, Wang Y, et al. Arachidonic Acid in Follicular Fluid of PCOS Induces Oxidative Stress in a Human Ovarian Granulosa Tumor Cell Line (KGN) and Upregulates GDF15 Expression as a Response. Front Endocrinol (Lausanne). 2022;13. doi:10.3389/FENDO.2022.865748
14. Aitken RJ, Wingate JK, de Iuliis GN, et al. Cis-unsaturated fatty acids stimulate reactive oxygen species generation and lipid peroxidation in human spermatozoa. J Clin Endocrinol Metab. 2006;91(10):4154-4163. doi:10.1210/JC.2006-1309
15. Laquer V, Dellinger RW, Mannering I, et al. 12-Hydroxyeicosatetraenoic acid levels are increased in actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2018;79(6):1152. doi:10.1016/J.JAAD.2018.05.1251
16. Reis MB, Pereira PAT, Caetano GF, et al. Lipoxin A4 encapsulated in PLGA microparticles accelerates wound healing of skin ulcers. PLoS ONE. 2017;12(7). doi:10.1371/JOURNAL.PONE.0182381