The actions of the ω-3 and ω-6 essential fatty acids (EFAs) are best characterized by their interactions; they cannot be understood separately. To meet Wikipedias quality standards, this article or section may require cleanup. ... Omega-6 fatty acids are fatty acids where the term omega-6 signifies that the first double bond in the carbon backbone of the fatty acid, counting from the end opposite the acid group, occurs in the sixth carbon-carbon bond. ...

For introductory details to this topic, including terminology and ω-3 / ω-6 nomenclature, see the main articles at Essential fatty acid and Eicosanoid.

Arachidonic acid (AA) is a 20-carbon ω-6 essential fatty acid. It sits at the head of the "arachidonic acid cascade" – more than twenty different signalling paths that control a bewildering array of bodily functions, but especially those functions involving inflammation and the central nervous system.(Piomelli, 2000) Most AA in the human body derives from dietary linoleic acid (another essential fatty acid, 18:3 ω-6), which comes both from vegetable oils and animal fats. Essential fatty acids, or EFAs, are fatty acids that are required in the human diet. ... In biochemistry, eicosanoids are a class of oxygenated hydrophobic cytokines that largely function as a autocrine and paracrine mediators. ... Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ... Signals in Biology refer to an electric quantity (voltage or current or field strength) whose modulation represents coded information about the biological source from which it comes, and are also known as Biopotentials. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... A diagram showing the CNS: 1. ... Linoleic acid (C18H32O2 or CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH) is a colourless liquid. ... It has been suggested that this article or section be merged with cooking oil. ... ...

In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. It is ingested from oily fish or derived from dietary α linolenic acid found in e.g., flax oil. DGLA (20:3 ω-6) provides a third, less prominent cascade. It derives from dietary GLA (18:3 ω-6) found in, e.g. borage oil. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less inflammatory essential fatty acids, especially the ω-3s, is associated with a variety of inflammation-related diseases. Eicosapentaenoic acid (more commonly known as EPA; C20H30O2, all-cis-fatty acid 20:5 omega-3) is a polyunsaturated fatty acid that acts as a precursor for prostaglandin-3, which inhibits platelet aggregation) and thromboxane-3 groups. ... Fish Oil is oil derived from fishes. ... Chemical structure of alpha-linolenic acid Linolenic acid is an 18-carbon polyunsaturated fatty acid with three double bonds. ... Binomial name Linum usitatissimum Linnaeus. ... Dihomo-gamma-linolenic acid (DGLA) is 20-carbon ω-3 fatty acid. ... Gamma-linolenic acid (GLA) is an omega-6 fatty acid that exists primarily in plant fats. ... Binomial name Borago officinalis L. Borage (Borago officinalis) is an annual herb native to central and eastern Europe. ...

The usual diet in industrial countries contains much less ω-3 fatty acids than the diet even a century ago, and that diet had much less ω-3 than the diet of early hunter-gatherers. This has been accompanied by increased rates of many diseases – the so-called diseases of civilization – that involve inflammatory processes. There is now very strong evidence (National Institute of Health, 2005) that several of these diseases are ameliorated by increasing dietary ω-3, and good evidence for many others. There is also more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders. Standard American Diet, or S.A.D., is a derogatory term used by naturalist health food advocates to describe the dietary habits of average Americans; advocates say that the average American has a diet that is relatively high in saturated fat, trans fat, chemical additives, and refined sugar. ... In anthropology, the hunter-gatherer way of life is that led by certain societies of the Neolithic Era based on the exploitation of wild plants and animals. ... Lifestyle diseases (also called diseases of longevity or diseases of civilization) are diseases that appear to increase in frequency as countries become more industrialized and people live longer. ...

Eicosanoid series nomenclature

For details on the metabolic pathways for eicosanoids in each series, see the main articles for prostaglandins (PG), thromboxanes (TX), prostacyclins (PGI) and leukotrienes (LK).

Eicosanoids are signalling molecules derived from the EFAs; they are a major pathway by which the EFAs act in the body. There are four classes of eicosanoid and two or three series within each class. Before discussing eicosanoid action, we will expalin the series nomenclature. In biochemistry, eicosanoids are a class of oxygenated hydrophobic cytokines that largely function as a autocrine and paracrine mediators. ... Chemical structure of prostaglandin E1 (PGE1). ... Thromboxane is a member of the family of lipids known as eicosanoids. ... Prostacyclin is a member of the family of lipid molecules known as eicosanoids. ... Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. ...

Cell's outer membranes contain phospholipid fat. Each phospholipid molecule contains two fatty acids. Some of these fatty acids are 20-carbon polyunsaturated essential fatty acids – AA, EPA or DGLA. In response to a variety of inflammatory signals, these EFAs are cleaved out of the phospholipid and released as free fatty acids. Next, the EFA is oxygenated (by either of two pathways), then further modified, yeilding the eicosanoids. (Dorlands, entry at "Prostaglandins")  Cyclooxygenase (COX) oxidation removes two C=C double bonds, leading to the TX, PG and PGI series. Lipoxygenase oxidation removes no C=C double bonds, and leads to the LK.(Cyberlipid Center.) Cells in culture, stained for keratin (red) and DNA (green). ... Drawing of a cell membrane A component of every biological cell, the selectively permeable cell membrane (or plasma membrane or plasmalemma) is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell. ... Two schematic representations of a phospholipid. ... This article or section is in need of attention from an expert on the subject. ... In chemistry, especially biochemistry, a fatty acid is a carboxylic acid (or organic acid), often with a long aliphatic tail (long chains), either saturated or unsaturated. ... Cyclooxygenase (COX) is an enzyme (EC 1. ... Covalently bonded hydrogen and carbon in a molecule of methane. ... Thromboxane is a member of the family of lipids known as eicosanoids. ... Chemical structure of prostaglandin E1 (PGE1). ... Prostacyclin is a member of the family of lipid molecules known as eicosanoids. ... Lipoxygenases are a class of enzymes which add oxygen to lipids. ... Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. ...

After oxidation, the eicosanoids are further modified, making a series. Members of a series are differentiated by an ABC... letter, and are numbered by the number of double bonds, which does not change within a series. For example, cyclooxygenase acts upon AA (with 4 double bonds) to generate the series-2 thromboxanes (TXA₂, TXB₂... ) each with two double bonds. Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ...

All the prostenoids are substituted prostanoic acids. Cyberlipid Center's Prostenoid page illustrates the parent compound and the rings associated with each series–letter.

Figure (1) shows these sequences for AA (20:4 ω-6). The sequences for EPA (20:5 ω-3) and DGLA (20:3 ω-6) are analagous. Eicosapentaenoic acid (more commonly known as EPA; C20H30O2, all-cis-fatty acid 20:5 omega-3) is a polyunsaturated fatty acid that acts as a precursor for prostaglandin-3, which inhibits platelet aggregation) and thromboxane-3 groups. ... Dihomo-gamma-linolenic acid (DGLA) is 20-carbon ω-3 fatty acid. ...

Gamma-linolenic acid (GLA) is an omega-6 fatty acid that exists primarily in plant fats. ... Dihomo-gamma-linolenic acid (DGLA) is 20-carbon ω-3 fatty acid. ... Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ... Eicosapentaenoic acid (more commonly known as EPA; C20H30O2, all-cis-fatty acid 20:5 omega-3) is a polyunsaturated fatty acid that acts as a precursor for prostaglandin-3, which inhibits platelet aggregation) and thromboxane-3 groups. ...

Arachidonic acid cascade in inflammation

Figure (1) The Arachidonic acid cascade, showing biosynthesis of AA's eicosanoid products. EFA and DGLA compete for the same pathways, moderating the actions of AA and its products.

In the arachidonic acid cascade, dietary linoleic acid (18:3 ω-6) is lengthened and desaturated to form arachidonic acid, esterified into the phospholipid fats in the cell membrane. Next, in response to many inflammatory stimuli, phospholipase is generated and cleaves this fat, releasing AA as a free fatty acid. AA can then be oxygenated and then further modified to form eicosanoids – autocrine and paracrine agents that bind receptors on the cell or its neighbors. Alternatively, AA can diffuse into the cell nucleus and interact with transcription factors to control DNA transcription for cytokines or other hormones. Image File history File links Eicosanoid synthesis. ... Linoleic acid (C18H32O2 or CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH) is a colourless liquid. ... General formula of an ester of a carboxylic acid. ... Two schematic representations of a phospholipid. ... Drawing of a cell membrane A component of every biological cell, the selectively permeable cell membrane (or plasma membrane or plasmalemma) is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell. ... In physiology, a stimulus is a detectable change in the internal or external environment. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... In chemistry, especially biochemistry, a fatty acid is a carboxylic acid (or organic acid), often with a long aliphatic tail (long chains), either saturated or unsaturated. ... In biochemistry, eicosanoids are a class of oxygenated hydrophobic cytokines that largely function as a autocrine and paracrine mediators. ... Autocrine signaling is a form of signalling in which a cell secretes a chemical messenger (called the autocrine agent) that signals the same cell. ... Paracrine signalling is a form of signalling in which the target cell is close to the signal releasing cell, and the signal chemical is broken down too quickly to be carried to other parts of the body. ... In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm that binds to a specific factor (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ... In cell biology, the nucleus (from Latin nucleus or nuculeus, kernel) is found in all eukaryotic cells and contains the nuclear genes which form most of the cells genetic material. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ... Transcription is the process through which a DNA sequence is enzymatically copied by an RNA polymerase to produce a complementary RNA. Or, in other words, the transfer of genetic information from DNA into RNA. In the case of protein-encoding DNA, transcription is the beginning of the process that ultimately... Cytokines are small protein molecules that regulate communication among immune system cells and between immune cells and those of other tissue types. ...

Mechanisms of ω-3 eicosanoid action

Figure (2) Essential fatty acid production and metabolism to form Eicosanoids

The eicosanoids from AA generally promote inflammation. Those from GLA (via DGLA) and from EPA are generally less inflamatory, or inactive, or even anti-inflamatory. (This generalization is qualified: an eicosanoid may be pro-inflamatory in one tissue and anti-inflamatory in another. See discussion of PGE₂ at (Calder, 2004))  Gamma-linolenic acid (GLA) is an omega-6 fatty acid that exists primarily in plant fats. ...

Figure (2) shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA.

Dietary ω-3 and GLA counter the inflamatory effects of AA's eicosanoids in three ways – displacement, competitive inhibition and direct counteraction. In biochemistry there are three ways in which certain chemical substances may reduce or prevent the activities of enzymes: competitive, non-competitive and uncompetitive inhibition. ...

Displacement

Dietary ω-3 decreases tissue concentrations of AA. Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue. (Medical News Study, 2005) Linolenic acid (18:3 ω-3) contributes to this by displacing linoleic acid (18:2 ω-6) from the elongase and desaturase enzymes that produce AA. EPA inhibits phospholipase A2's release of AA from cell membrane.(Su et al 2003)  Other mechinisms involving the transport of EFAs may also play a role. Chemical structure of alpha-linolenic acid Linolenic acid is an 18-carbon polyunsaturated fatty acid with three double bonds. ... Linoleic acid (C18H32O2 or CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH) is a colourless liquid. ... A Desaturase is an enzyme which removes two hydrogen atoms from an organic compound, creating a carbon/carbon double bond. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ...

The reverse is also true – high dietary lineolate decreases the body's conversion of α-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for α-linolenic acid than it does linoleic acid.(Phinney, 1990)

Competitive Inhibition

DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosonoids. For example, dietary GLA increases tissue DGLA and lowers TXB₂. (Guivernau, 1994) (Karlstaad, 1993)   Likewise, EPA inhibits the production of series-2 PG and TX. (Calder, 2004) Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs.(Belch 2000) 

Counteraction

Some DGLA and EPA derived eicosonoids counteract their AA derived counterparts. For example, DGLA yields PGE₁, which powerfully counteracts PGE₂. (Fan, 1998)  EPA yields the antiaggregatory prostacyclin PGI₃ (Fischer, 1985) It also yields the leuokotriene LKB₅ which vitiates the action of the AA-derived LKB₄. (Prescott, 1984)

The paradox of dietary GLA

Dietary linoleic acid (LA, 18:2 ω-6) is inflammatory. In the body, LA is desaturated to form GLA (18:3 ω-6). But dietary GLA is anti-inflammatory. How is this possible? Linoleic acid (C18H32O2 or CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH) is a colourless liquid. ...

Some observations paritally explain this paradox. LA competes with α-linolenic acid, (LNA, 18:3 ω-3) for Δ6-desaturase, and thereby eventually inhibits formation of anti-inflammatory EPA (20:5 ω-3). In contrast, GLA does not complete for Δ6-desaturase. GLA's elongation product DGLA (20:3 ω-6) competes with 20:4 ω-3 for the Δ5-desaturase, and it might be expected that this would make GLA inflammatory, but it is not. Why? Perhaps because this step isn't rate-detrmining. Δ6-desaturase does appear to be the rate-limiting step; 20:4 ω-3 does not significantly accumulate in bodily lipids. Linolenic acid is an 18-carbon polyunsaturated fatty acid with three double bonds. ... The rate-determining step is a chemistry term for the slowest step in a chemical reaction. ...

DGLA inhibits inflammation through both competitive inhibition and direct counteraction (see above.) Dietary GLA leads to sharply increased DGLA in the white blood cells' membranes, where LA does not. This may reflect white blood cells' lack of desaturase.(Fan, Chapkin 1998)

It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small, (Karlstad et al, 1993)  The empirical obseration of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate.(Stone et al, 1979)

The arachidonic acid cascade in the CNS

"The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with." – Piomelli, 2000

The arachidonic acid cascade proceeds somewhat differently in the brain. Neurohormones, neuromodulators or neurotransmitters act as first messengers. They activate phospholipidase to release AA from neuron cell membranes as a free fatty acid. During its short lifespan, free AA may affect the activity of the neuron's ion channels and protein kinases. Or it may be metabolized to form eicosanoids, epoxyeicosatrienoic acids (EETs), neuroprotectin D or various endocannabinoids (anandamide and its analogs.) Any hormone produced by neurosecretory cells, usually in the brain. ... A neuromodulator is a substance other than a neurotransmitter, released by a neuron at a synapse and conveying information to adjacent or distant neurons, either enhancing or damping their activities. ... Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. ... Drawing by Santiago Ramón y Cajal of cells in the pigeon cerebellum. ... Another, unrelated ion channeling process is part of ion implantation. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ... Cannabinoids are a group of chemicals which activate the bodys cannabinoid receptors. ... Anandamide, also known as arachidonoylethanolamine or AEA, is a naturally occurring endogenous cannabinoid neurotransmitter found in the brain of animals, as well as other organs. ...

The actions of eicosanoids within the brain are not as well characterized as they are in inflammation. It is theorized that they act within the neuron as second messengers controlling presynaptic inhibition and the activation of protein kinase C. They also act as paracrine mediators, acting across synapses to nearby cells. Although detail on the effects of these signals is scant, (Piomelli, 2000) comments In biology, second messengers are low-weight diffusible molecules that are used in signal transduction to relay signals within a cell. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ...

Neurons in the CNS are organized as interconnected groups of functionally related cells (e.g., in sensory systems). A diffusible factor released from a neuron into the interstitial fluid, and able to interact with membrane receptors on adjacent cells, would be ideally used to "synchronize" the activity of an ensemble of interconnected neural cells. Furthermore, during development and in certain forms of learning, postsynaptic cells may secrete regulatory factors which diffuse back to the presynaptic component, determining its survival as an active terminal, the amplitude of its sprouting, and its efficacy in secreting neurotransmitters—a phenomenon known as retrograde regulation. The participation of arachidonic acid metabolites in retrograde signaling and in other forms of local modulation of neuronal activity has been proposed.

The EPA and DGLA cascades are also present in the brain and their eicosanoid metabolites have been detected. The ways in which these differently affect mental and neural processes are not nearly as well characterized as are the effects in inflammation.

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