User:David.Throop/Essential fatty acid interactions

From Wikipedia, the free encyclopedia

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.

[edit] 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.

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.)

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.

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.

[edit] 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.

[edit] 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)) 

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.

[edit] 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.

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)

[edit] 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) 

[edit] 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)

[edit] 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 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-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 obseration of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate.(Stone et al, 1979)

[edit] 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.)

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.

[edit] Sources

• Belch,Jill JF and Alexander Hill (January 2000). Evening primrose oil and borage oil in rheumatologic conditions. Retrieved on February 12, 2006. 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."

• Calder, Philip C. (September 2004). n-3 Fatty Acids and Inflammation – New Twists in an Old Tale. Retrieved on February 8, 2006. Invited review article, PUFA Newsletter.

• Cyberlipid Center. Polyenoic fatty acids. Retrieved on February 11, 2006.
• Cyberlipid Center. Prostanoids. Retrieved on February 11, 2006.

• De Caterina, R and Basta, G. n-3 Fatty acids and the inflammatory response – biological background. Retrieved on February 10, 2006.

• Dorlands Medical Dictionary entry for 'Prostaglandin'. Retrieved on October 23, 2005.

• Fischer S, Weber PC (Sep 1985). Thromboxane (TX)A3 and prostaglandin (PG)I3 are formed in man after dietary eicosapentaenoic acid: identification and quantification by capillary gas chromatography-electron impact mass spectrometry.. Retrieved on February 10, 2006. PubMed abstract

• Guivernau M, Meza N, Barja P, Roman O. (Nov 1994). Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production.. Retrieved on 4 February 2005. PubMed: 7846101.
  • GLA decreases triglycerides, LDL, increases HDL, decreases TXB₂ and other inflamatory markers. Review article; human and rat studies.

• Fan, Yang-Yi and Robert S. Chapkin (9 September 1998). Importance of Dietary gamma -Linolenic Acid in Human Health and Nutrition. Retrieved on February 3, 2006.
  • "[D]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."

• Jefo Nutrition. Polyunsaturated fatty acids of the ω-3 type in swine nutrition. Retrieved on February 16, 2006.

• Karlstad MD, DeMichele SJ, Leathem WD, Peterson MB. (Nov 1993). Effect of intravenous lipid emulsions enriched with gamma-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after burn and endotoxin injury in rats. Retrieved on February 6, 2006.
  • IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB₂.

• Medical Study News (25-May-2005). Brain fatty acid levels linked to depression. Retrieved on February 10, 2006.
  • Who were in turn citing Pnina Green, Iris Gispan-Herman and Gal Yadid (June 2005). Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression. Retrieved on February 10, 2006.

• National Institute of Health (August 1, 2005). Omega-3 fatty acids, fish oil, alpha-linolenic acid. Retrieved on March 26, 2006.

• Phinney,SD , RS Odin, SB Johnson and RT Holman (1990). Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans. Retrieved on February 11, 2006.
  • "[D]ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."

• Piomelli, Daniele (2000). Arachidonic Acid. Neuropsychopharmacology: The Fifth Generation of Progress. Retrieved on 2006-03-03.

• Prescott, Scott (1984). The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils.. Retrieved on February 16, 2006.
  • EPA LT{A,B,C,D}₅

• Stone KJ, Willis AL, Hart WM, Kirtland SJ, Kernoff PB, McNicol GP. (1979 Feb). The metabolism of dihomo-gamma-linolenic acid in man.. Retrieved on February 15, 2006. PubMed abstract
  • Administering DGLA → PGE₁ but doesn't increase PGE₂

• KP Su, SY Huang, CC Chiu, WW Shen (2003). Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled …. Retrieved on February 22, 2006.