Arachidonic acid

What is Arachidonic Acid

Arachidonic acid is a C20-long-chain polyunsaturated fatty acid with four (Z)-double bonds at positions 5, 8, 11, and 14. Arachidonic acid is an isomer of the eicosapentaenoic acid family. It has known roles as a human, mouse, and Daphnia galeata metabolite. This metabolite is also a carboxylesterase inhibitor and a procoagulant, which drives platelet aggregation and blood coagulation¹. Arachidonic acid is a natural product found in Agaricus blazei, Mortierella hygrophila, and other organisms. Exogenous arachidonic acid plays a significant role in various physiological processes, including Ca²⁺ signaling in non-excitable cells, platelet aggregation, immune functions, inflammatory responses, and neurological development. It is also found in animal and human fat as well as in the liver, brain, and glandular organs. Arachidonic acid can be synthesized by the elongation and dehydration of linoleic acid, a short essential fatty acid.

Arachidonic acid is incorporated in membrane phospholipids in the cytosol, adjacent to the endoplasmic reticulum membrane, which is studded with the proteins necessary for phospholipid synthesis and allocation to the diverse biological membranes. Arachidonic acid on the inner surface of cell membranes is hydrolyzed by phospholipase A2, cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes to a variety of lipid mediators, including prostanoids, leukotrienes, epoxyeicosatrienoic acids, dihydroxyeicosatetraenoic acid, eicosatetraenoic acids, and lipoxins. Arachidonic acid and it’s downstream metabolic cascade play key roles in cardiovascular diseases, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, and more².

Arachidonic acid metabolites and inflammation

Arachidonic acid and its metabolites are generally considered proinflammatory lipid mediators, playing a crucial role in the arachidonic acid cascade. Tumor necrosis factor alpha, and other inflammatory markers, can stimulate arachidonic acid metabolism. Elevated arachidonic acid levels in preterm infants or adults could be a sign of systemic inflammation and nonalcoholic fatty liver disease, respectively. In addition, arachidonic acid–derived hydroxyl metabolites are associated with air pollution and can exacerbate the body’s inflammatory response to pollution³.

Arachidonic acid treatment has also been shown to ease acute inflammation. For example, in patients with obesity, arachidonic acid treatment downregulates proinflammatory markers and pathways. Furthermore, arachidonic acid treatment can effectively reduce adipocyte inflammation induced by a high-fat diet in obese mice. Mechanistically, arachidonic acid has been shown to block Toll-like receptor 4 (TLR4) activation in cardiomyocytes and macrophages. Arachidonic acid binds to the TLR4 coreceptor myeloid differentiation factor 2 (MD2), which inhibits the formation of the active TLR4–MD2 complex and downstream proinflammatory cytokine release. Diabetic rats treated with arachidonic acid showed lower systemic inflammation. However, whether this response is driven directly by arachidonic acid or one of its downstream metabolites remains unknown. Arachidonic acid metabolites, generated through the actions of oxygenases such as cyclooxygenase, lipoxygenase, and cytochrome P450, play significant roles in regulating numerous physiological processes and are associated with immune responses and inflammatory states. Additional research is needed to investigate whether arachidonic acid interacts with any other inflammatory receptors to mediate its effects^4,5.

Arachidonic acid and cardiovascular disorders

High arachidonic acid levels are associated with many cardiovascular diseases, such as atherosclerotic cardiovascular disease, venous thromboembolism, and ischemic heart disease. Increased dietary intake of arachidonic acid can affect platelet aggregation and platelet fatty acid composition, which plays a significant role in various physiological functions. Mechanistically, arachidonic acid may induce oxidative stress by altering nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–mediated production of reactive oxygen species. NADPH oxidase activation may induce systemic inflammation as well as lead to atherosclerotic cardiovascular disorders. In chronic obstructive pulmonary disease, arachidonic acid increases inflammation but inhibits extracellular matrix protein expression, which could lead to decreased fibrosis. Further research is needed to define how arachidonic acid impacts the development and progression of each distinct cardiovascular disease⁵.

Arachidonic acid and neurological disorders

In many neurological disorders, dietary supplementation of arachidonic acid has beneficial effects on cognition. Children with autism often display low blood arachidonic acid levels. However, after supplementing autistic children’s meals with dietary fatty acids, including arachidonic acid, they showed cognitive improvements. Furthermore, arachidonic acid supplements also improved cognitive functions in elderly patients. Mechanistically, arachidonic acid may drive neural stem or progenitor cell proliferation and differentiation to mature neurons, which could lead to improved axonal signaling. The fatty acid composition, particularly the presence of arachidonic acid, plays a crucial role in neurological development. However, these studies were limited in scope and thus more research is needed to determine if arachidonic acid could be a viable therapeutic for individuals with neurological conditions^6,7.

Arachidonic acid and cancer

Arachidonic acid and many of its metabolites regulate carcinogenesis, as well as tumor cell proliferation, chemotaxis, migration, and apoptosis. Tumor cells exposed to arachidonic acid can adopt an abnormal shape, which improves cell motility and promotes metastasis. Mechanistically, arachidonic acid can inhibit immune cell activation by disrupting lipid raft structures in their plasma membranes. Indeed, 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 control⁸.

Increased risk of prostate cancer has been linked to single nucleotide polymorphisms in genes involved in the arachidonic acid catabolic pathway. Pharmacologically inhibiting arachidonic acid catabolism improved outcomes and reduced tumor size in animal models of brain, kidney, and breast cancer. However, further studies are needed to examine if arachidonic acid inhibition is a viable cancer therapeutic⁹.

Free arachidonic acid has also been shown to inhibit carcinogenesis. In tumor cells, arachidonic acid can promote tumor cell death by inducing cell membrane lipid peroxidation. Furthermore, arachidonic acid may drive cancer cell death by upregulating NADPH oxidase expression, which catalyzes reactive oxygen species generation, as well as caspase activation. Additional research is needed in animal models and humans to fully understand the role that arachidonic acid plays in various types of cancer¹⁰.

Dietary arachidonic acid and muscle

Within skeletal muscle, arachidonic acid comprises 15–17% of the total fatty acids. In humans, arachidonic acid may promote skeletal muscle growth. To this end, increasing dietary arachidonic acid may increase intramuscular, post-exercise anabolic signaling. Furthermore, prolonged supplemental arachidonic acid can decrease muscle inflammation by inhibiting the proinflammatory cytokine, IL-6, thus preventing chronic inflammation that could lead to muscle mass loss. Individuals given prolonged supplementation of arachidonic acid also show reduced fat mass, but not muscle hypertrophy. Additional studies incorporating more individuals are needed to clearly elucidate connections between muscle and arachidonic acid¹¹.

Arachidonic acid supplementation and fertility

Arachidonic acid plays a role in reproduction, including ovulation, menstruation, pregnancy, and childbirth. Furthermore, oocyte maturation and DNA methylation in embryos require arachidonic acid catabolism. Elevated arachidonic acid levels in oocyte follicular fluid, increases oxidative stress and induces growth/differentiation factor-15 expression, which can suppress osteoblast differentiation and new bone development in the developing embryo. Bovine embryos treated with low doses of arachidonic acid showed increased survival; however, those treated with high doses showed decreased survival. To elucidate if these dose-dependent effects occur in humans, further studies and clinical trials are needed¹². The importance of arachidonic acid continues after childbirth. For example, arachidonic acid is the most abundant long-chain polyunsaturated fatty acid in human milk, where it is one of the key building blocks of triglycerides. Furthermore, arachidonic acid is crucial for fetal development, especially the nervous, skeletal muscle, and immune systems.

Arachidonic acid also plays a role in male fertility. This metabolite is present in both sperm membranes and the testis microenvironment. However, sperm exposure to excessive arachidonic acid can lead to DNA damage and reduced sperm motility. Furthermore, high testes arachidonic acid levels positively correlate with defective sperm. In this situation, arachidonic acid may promote the generation of reactive molecular oxygen species. Collectively, these data suggest that inhibiting arachidonic acid synthesis or promoting arachidonic acid catabolism may be viable therapeutic options for treating male infertility; however, further research in animals and humans is needed¹³.

Arachidonic acid and research

As of June 2024, there are over 6,415 citations for arachidonic acid in research publications (excluding books and documents) on PubMed. As researchers continue to unravel the pharmacological and physiological mechanisms of arachidonic acid 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. Additionally, understanding the effects of arachidonic acid on tissue fatty acid composition is crucial, as it impacts lipid composition in plasma, cellular functions, and immune responses.

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. Wang B, Wu L, Chen J, et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther. 2021;6(1). doi:10.1038/S41392-020-00443-W
3. 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
4. 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
5. Zhang T, Zhao J, and 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
6. Yui K, Koshiba M, Nakamura S, et al. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial. J Clin Psychopharmacol. 2012;32(2):200-206. doi:10.1097/JCP.0B013E3182485791
7. Tokuda H, Kontani M, Kawashima H, et al. Differential effect of arachidonic acid and docosahexaenoic acid on age-related decreases in hippocampal neurogenesis. Neurosci Res. 2014;88(C):58-66. doi:10.1016/J.NEURES.2014.08.002
8. 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
9. Amirian ES, Ittmann MM, and Scheurer ME. Associations between arachidonic acid metabolism gene polymorphisms and prostate cancer risk. The Prostate. 2011;71(13):1382-1389. doi:10.1002/PROS.21354
10. Dai J, Shen J, Pan W, et al. Effects of polyunsaturated fatty acids on the growth of gastric cancer cells in vitro. Lipids Health Dis. 2013;12(1). doi:10.1186/1476-511X-12-71
11. de Souza EO, Lowery RP, Wilson JM, et al. Effects of Arachidonic Acid Supplementation on Acute Anabolic Signaling and Chronic Functional Performance and Body Composition Adaptations. PloS ONE. 2016;11(5). doi:10.1371/JOURNAL.PONE.0155153
12. 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
13. 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