Gourt Home::Gourt :: Essential fatty acid interactions
The actions of the ω-3 and ω-6 essential fatty acids (EFAs) are best characterized by their interactions; they cannot be understood separately.
- 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.
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.
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.
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 explain the series nomenclature.
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, yielding 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.)
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 action upon AA (with 4 double bonds) leads to the series-2 thromboxanes (TXA2, TXB2... ) each with two double bonds. Cyclooxygenase action on EPA (with 5 double bonds) leads to the series-3 thromboxanes (TXA3, TXB3... ) each with three double bonds.
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 analogous.
| Dietary Essential Fatty Acid | Abbr | Formula ω carbons:double bonds |
Eicosanoid product series | ||
|---|---|---|---|---|---|
| TX PG PGI |
LK | Effects | |||
| Gamma-linolenic acid via Dihomo gamma linolenic acid |
GLA DGLA |
ω-6 18:3 ω-6 20:3 |
series-1 | series-3 | less inflammatory |
| Arachidonic acid | AA | ω-6 20:4 | series-2 | series-4 | more inflammatory |
| Eicosapentaenoic acid | EPA | ω-3 20:5 | series-3 | series-5 | less inflammatory |
All the prostenoids are substituted prostanoic acids. Cyberlipid Center's Prostenoid page illustrates the parent compound and the rings associated with each series–letter.
Arachidonic acid cascade in inflammation
In the arachidonic acid cascade, dietary linoleic acid (18:2 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.
Mechanisms of ω-3 eicosanoid action
The eicosanoids from AA generally promote inflammation. Those from GLA (via DGLA) and from EPA are generally less inflammatory, or inactive, or even anti-inflammatory. (This generalization is qualified: an eicosanoid may be pro-inflammatory in one tissue and anti-inflammatory in another. See discussion of PGE2 at (Calder, 2004))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 inflammatory effects of AA's eicosanoids in three ways – displacement, competitive inhibition and direct counteraction.
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 mechanisms involving the transport of EFAs may also play a role.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?Some observations partially 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-determining. Δ6-desaturase does appear to be the rate-limiting step; 20:4 ω-3 does not significantly accumulate in bodily lipids.
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 observation of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate. (Stone et al, 1979)
The arachidonic acid cascade in the CNS
| Arachidonic Acid Cascade | ||
|---|---|---|
| In inflammation | In the brain | |
| Major effect on | Inflammation in tissue | Neuronal excitability |
| AA released from | White blood cells | Neurons |
| Triggers for AA release | Inflammatory stimuli | Neurotransmitters, neurohormones and neuromdulators |
| Intracellular effects on | DNA transcription of cytokines and other mediators of inflammation | Activity of ion channels and protein kinases |
| Metabolized to form | Eicosanoids, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) | Eicosanoids, neuroprotectin D, EETs and some endocannabinoids |
"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.)
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
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.
Sources
- PubMed cite.
- "DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation."
- Invited review article, PUFA Newsletter.
- PubMed abstract
- PubMed: 7846101.
- GLA decreases triglycerides, LDL, increases HDL, decreases TXB2 and other inflammatory markers. Review article; human and rat studies.
-
- "*ietary GLA increases the content of its elongase product, dihomo-gamma linolenic acid (DGLA), within cell membranes without concomitant changes in arachidonic acid (AA). Subsequently, upon stimulation, DGLA can be converted by inflammatory cells to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E1. This is noteworthy because these compounds possess both anti-inflammatory and antiproliferative properties."
-
- IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB2.
-
- Who were in turn citing
-
- "*ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."
-
- EPA LT{A, B,C, D}5
- PubMed abstract
- Administering DGLA → PGE1 but doesn't increase PGE2
"Essential fatty acid interactions"