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Nature Chemical Biology Jan 2017Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of...
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
Topics: Animals; Arachidonic Acid; Cell Death; Cell Line; Coenzyme A Ligases; Fatty Acids, Unsaturated; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phospholipids
PubMed: 27842066
DOI: 10.1038/nchembio.2238 -
International Journal of Molecular... Nov 2021Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP)... (Review)
Review
Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP) enzymes, and lipid oxygenase (LOX) pathways to regulate complex cardiovascular function under physiological and pathological conditions. Various AA metabolites include prostaglandins, prostacyclin, thromboxanes, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. The AA metabolites play important and differential roles in the modulation of vascular tone, and cardiovascular complications including atherosclerosis, hypertension, and myocardial infarction upon actions to different receptors and vascular beds. This article reviews the roles of AA metabolism in cardiovascular health and disease as well as their potential therapeutic implication.
Topics: Animals; Arachidonic Acid; Cardiovascular Diseases; Cardiovascular System; Humans; Lipid Metabolism; Prostaglandins
PubMed: 34769460
DOI: 10.3390/ijms222112029 -
Proceedings of the National Academy of... Dec 2020Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism,...
Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.
Topics: Arachidonic Acid; Carbolines; Cell Line, Tumor; DNA Methylation; Delta-5 Fatty Acid Desaturase; Enhancer Elements, Genetic; Fatty Acid Desaturases; Fatty Acid Elongases; Fatty Acids, Unsaturated; Ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Lipid Metabolism; Promoter Regions, Genetic; Stomach Neoplasms
PubMed: 33288688
DOI: 10.1073/pnas.2006828117 -
International Journal of Molecular... Dec 2020The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to... (Review)
Review
The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women's ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.
Topics: Arachidonic Acid; Female; Humans; Linoleic Acid; Pregnancy; Pregnancy Complications; Reproduction
PubMed: 33348841
DOI: 10.3390/ijms21249628 -
Cell Chemical Biology Mar 2019The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not...
The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.
Topics: Animals; Arachidonic Acid; Cell Line; Cell Membrane; Coenzyme A Ligases; Fatty Acids, Monounsaturated; Ferroptosis; Lipid Droplets; Lipids; Mice; Oxidation-Reduction; Phospholipid Hydroperoxide Glutathione Peroxidase; Reactive Oxygen Species
PubMed: 30686757
DOI: 10.1016/j.chembiol.2018.11.016 -
Nutrients Feb 2020Breastfeeding is universally recommended as the optimal choice of infant feeding and consequently human milk has been extensively investigated to unravel its unique... (Review)
Review
Breastfeeding is universally recommended as the optimal choice of infant feeding and consequently human milk has been extensively investigated to unravel its unique nutrient profile. The human milk lipid composition is unique and supplies specifically long-chain polyunsaturated fatty acids (LC-PUFAs), in particular, arachidonic acid (ARA, 20:4-6) and docosahexaenoic acid (DHA, 22:6-3). Arachidonic acid (ARA) is the most predominant long-chain polyunsaturated fatty acid in human milk, albeit at low concentrations as compared to other fatty acids. It occurs predominantly in the triglyceride form and to a lesser extent as milk fat globule membrane phospholipids. Human milk ARA levels are modulated by dietary intake as demonstrated by animal and human studies and consequently vary dependent on dietary habits among mothers and regions across the globe. ARA serves as a precursor to eicosanoids and endocannabinoids that also occur in human milk. A review of scientific and clinical studies reveals that ARA plays an important role in physiological development and its related functions during early life nutrition. Therefore, ARA is an important nutrient during infancy and childhood and, as such, appropriate attention is required regarding its nutritional status and presence in the infant diet. Data are emerging indicating considerable genetic variation in encoding for desaturases and other essential fatty acid metabolic enzymes that may influence the ARA level as well as other LC-PUFAs. Human milk from well-nourished mothers has adequate levels of both ARA and DHA to support nutritional and developmental needs of infants. In case breastfeeding is not possible and infant formula is being fed, experts recommend that both ARA and DHA are added at levels present in human milk.
Topics: Animals; Arachidonic Acid; Docosahexaenoic Acids; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Milk, Human
PubMed: 32121018
DOI: 10.3390/nu12030626 -
International Journal of Molecular... May 2023Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF,... (Review)
Review
Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE and PGE. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.
Topics: Animals; Male; Humans; Semen; Arachidonic Acid; Prostaglandins E; Prostaglandins; Fertility
PubMed: 37175913
DOI: 10.3390/ijms24098207 -
Prostaglandins & Other Lipid Mediators Nov 2018Isolevuglandins are 4-ketoaldehydes formed by peroxidation of arachidonic acid. Isolevuglandins react rapidly with primary amines including the lysyl residues of... (Review)
Review
Isolevuglandins are 4-ketoaldehydes formed by peroxidation of arachidonic acid. Isolevuglandins react rapidly with primary amines including the lysyl residues of proteins to form irreversible covalent modifications. This review highlights evidence for the potential role of isolevuglandin modification in the disease processes, especially atherosclerosis, and some of the tools including small molecule dicarbonyl scavengers utilized to assess their contributions to disease.
Topics: Arachidonic Acid; Atherosclerosis; Cardiovascular Diseases; Humans; Lipid Peroxidation; Lipids
PubMed: 30296489
DOI: 10.1016/j.prostaglandins.2018.10.002 -
Archives of Medical Research Jan 2021Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and... (Review)
Review
Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and treatment of COVID-19. This proposal is supported by the observation that (i) macrophages and T cells (including NK cells, cytotoxic killer cells and other immunocytes) release AA and other BALs especially in the lungs to inactivate various microbes; (ii) pro-inflammatory metabolites prostaglandin E2 (PGE2) and leukotrienes (LTs) and anti-inflammatory lipoxin A4 (LXA4) derived from AA (similarly, resolvins, protectins and maresins derived from eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) facilitate the generation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages respectively; (iii) AA, PGE2, LXA4 and other BALs inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) synthesis; (iv) mesenchymal stem cells (MSCs) that are of benefit in COVID-19 elaborate LXA4 to bring about their beneficial actions and (v) subjects with insulin resistance, obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and the elderly have significantly low plasma concentrations of AA and LXA4 that may render them more susceptible to SARS-CoV-2 infection and cytokine storm that is associated with increased mortality seen in COVID-19. Statins, colchicine, and corticosteroids that appear to be of benefit in COVID-19 can influence BALs metabolism. AA, and other BALs influence cell membrane fluidity and thus, regulate ACE-2 (angiotensin converting enzyme-2) receptors (the ligand through which SARS-CoV2 enters the cell) receptors. These observations lend support to the contention that administration of BALs especially, AA could be of significant benefit in prevention and management of COVI-19 and other enveloped viruses.
Topics: Animals; Arachidonic Acid; COVID-19; Cytokines; Humans; Lipids; Rats; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32981754
DOI: 10.1016/j.arcmed.2020.09.006 -
Journal of Lipid Research Jul 2016Arachidonic acid and esterified arachidonate are ubiquitous components of every mammalian cell. This polyunsaturated fatty acid serves very important biochemical roles,... (Review)
Review
Arachidonic acid and esterified arachidonate are ubiquitous components of every mammalian cell. This polyunsaturated fatty acid serves very important biochemical roles, including being the direct precursor of bioactive lipid mediators such as prostaglandin and leukotrienes. This 20 carbon fatty acid with four double bonds was first isolated and identified from mammalian tissues in 1909 by Percival Hartley. This was accomplished prior to the advent of chromatography or any spectroscopic methodology (MS, infrared, UV, or NMR). The name, arachidonic, was suggested in 1913 based on its relationship to the well-known arachidic acid (C20:0). It took until 1940 before the positions of the four double bonds were defined at 5,8,11,14 of the 20-carbon chain. Total synthesis was reported in 1961 and, finally, the configuration of the double bonds was confirmed as all-cis-5,8,11,14. By the 1930s, the relationship of arachidonic acid within the family of essential fatty acids helped cue an understanding of its structure and the biosynthetic pathway. Herein, we review the findings leading up to the discovery of arachidonic acid and the progress toward its complete structural elucidation.
Topics: Arachidonic Acid; Biochemistry; Fatty Acids, Unsaturated; History, 20th Century; History, 21st Century; Humans
PubMed: 27142391
DOI: 10.1194/jlr.R068072