Essential fatty acid interactions: Difference between revisions

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{{for|introductory details to this topic, including terminology and ω-3 / ω-6 nomenclature|Essential fatty acid|Eicosanoid}}

The actions of the [[Omega-3 fatty acid|ω-3]] and [[Omega-6 fatty acid|ω-6]] '''essential fatty acids''' (EFAs) are best characterized by their '''interactions'''; they cannot be understood separately.

[[File:Fatty Acid Breakdown.jpg|alt=Fatty Acid breakdown|thumb|Fatty acid breakdown]]

There is a wide variety of [[fatty acid|'''fatty acids''']] found in nature. Two classes of fatty acids are considered essential, the [[Omega-3 fatty acid|omega-3]] and [[Omega-6 fatty acid|omega-6]] fatty acids. Essential fatty acids are necessary for humans but cannot be synthesized by the body and must therefore be obtained from food. Omega-3 and omega-6 are used in some [[Cell signaling|cellular signaling pathways]] and are involved in mediating [[inflammation]], protein synthesis, and [[metabolic pathways]] in the human body.

: ''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 &omega;-6 essential fatty acid, .<ref name=Cunnane>{{Citecite journal web|author vauthors = Cunnane, StephenSC C| title =Essential FattyProblems Acidswith essential fatty acids: Timetime for a Newnew Paradigmparadigm? |work journal =PUFA NewsletterProgress in Lipid Research |year volume =June, 200542 |accessdate issue =2006-03-14 6 |url pages =http://www.fatsoflife.com/pufa/article.asp?nid 544–568 | date =1&edition November 2003 | pmid =arch&id 14559071 | doi =266 10.1016/S0163-7827(03)00038-9 }}</ref>. It sits at the head of the '''"arachidonic acid cascade,"''' &ndash; morewhich thaninitiates twenty20 different [[signals (biology)|signalling pathspathways]] that control a bewilderingwide array of bodilybiological functions, but especially those functions involvingincluding [[inflammation]], [[cell growth]], and the [[central nervous system]], .<ref name=Piomelli>{{Cite web |author=Piomelli, Daniele |title=Arachidonic Acid |url= http://www.acnp.org/g4/GN401000059/Default.htm | year= 2000 |accessdateaccess-date=2006-03-03 |work=Neuropsychopharmacology: The Fifth Generation of Progress |url-status=dead |archive-url=https://web.archive.org/web/20060715122827/http://www.acnp.org/g4/GN401000059/Default.htm |archive-date=2006-07-15 }}</ref>. Most AA in the human body derivesis derived from dietary [[linoleic acid]] (another essential fatty acid, 18:2 &omega;ω-6), which comesis bothfound fromin [[nut (fruit)|nuts]], [[seeds]], [[vegetable oil]]s, and [[animal fat]]s.<ref>{{Cite journal| vauthors = Freitas HR |date=2017-08-25|title=Chlorella vulgaris as a Source of Essential Fatty Acids and Micronutrients: A Brief Commentary |journal=The Open Plant Science Journal|volume=10|issue=1|pages=92–99|doi= 10.2174/1874294701710010092 |doi-broken-date=12 July 2025 |doi-access=free|issn=1874-2947}}</ref><ref>{{cite journal | vauthors = Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA | title = Polyunsaturated fatty acids and endocannabinoids in health and disease | journal = Nutritional Neuroscience | volume = 21 | issue = 10 | pages = 695–714 | date = December 2018 | pmid = 28686542 | doi = 10.1080/1028415X.2017.1347373 | s2cid = 40659630 }}</ref>

== Eicosanoid series nomenclature ==

In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. [[Eicosapentaenoic acid|EPA (20:5 &omega;-3)]] provides the most important competing cascade. It is ingested from [[Fish oil|oily fish]] or derived from dietary [[Linolenic acid|a linolenic acid]] found in e.g., [[Flax|flax oil]]. [[Dihomo-gamma-linolenic acid|DGLA (20:3 &omega;-6)]] provides a third, less prominent cascade. It derives from dietary [[Gamma-linolenic acid|GLA (18:3 &omega;-6)]] found in, e.g. [[Borage|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 &omega;-3s, is associated with a variety of inflammation-related diseases.

{{hatnote|For details on the metabolic pathways for [[eicosanoid]]s in each series, see the main articles for [[prostaglandin]]s (PG), [[thromboxane]]s (TX), [[prostacyclin]]s (PGI) and [[leukotriene]]s (LK)}}

Eicosanoids are signaling molecules derived from the essential fatty acids (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. The [[Cell membrane|plasma membranes]] of [[Cell (biology)|cells]] contain [[phospholipid]]s, composed of a hydrophilic phosphate head and two hydrophobic [[fatty acid]] tails. Some of these fatty acids are 20-carbon [[PUFA|polyunsaturated]] essential fatty acids (AA, EPA, or DGLA). EFAs are cleaved out of the phospholipid and released as free fatty acids. The EFA is oxygenated (by either of two pathways) and further modified, yielding the eicosanoids.

Today, the [[Standard American Diet|usual diet in industrial countries]] contains much less &omega;-3 fatty acids than the diet of a century ago. The diet from a century ago had much less &omega;-3 than the diet of early [[hunter-gatherer]]s, <ref name=Simopoulos>{{cite journal |author=Simopoulos A |title=Evolutionary aspects of diet and essential fatty acids |url=http://eurheartjsupp.oxfordjournals.org/cgi/reprint/3/suppl_D/D8.pdf| journal=World Rev Nutr Diet |volume=88 |issue= |pages=18-27 |year= 2001 |id=PMID 11935953}}</ref>. We can also look at the ratio of &omega;-3 to &omega;-6 in comparisons of their diets. These changes have been accompanied by increased rates of many diseases &ndash; the so-called [[Lifestyle diseases|diseases of civilization]] &ndash; that involve inflammatory processes. There is now very strong evidence <ref name=National>{{cite web| author=National Institute of Health| url= http://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html | title=Omega-3 fatty acids, fish oil, alpha-linolenic acid | accessyear=2006|accessdate=March 26| date= August 1, 2005}}</ref> that several of these diseases are ameliorated by increasing dietary &omega;-3, and good evidence for many others. There is also more preliminary evidence showing that dietary &omega;-3 can ease symptoms in several psychiatric disorders.<ref name=decat>{{cite web|author= De Caterina, R and Basta, G|title= n-3 Fatty acids and the inflammatory response &ndash; biological background| url = http://eurheartjsupp.oxfordjournals.org/cgi/reprint/3/suppl_D/D42.pdf|accessdate= June 1|accessyear = 2006}}</ref>

After oxidation, the eicosanoids are further modified, making a ''series''. Members of a series are differentiated by a letter and are numbered by the number of double bonds, which does not change within a series. For example, cyclooxygenase action upon [[arachidonic acid|AA]] (with 4 double bonds) leads to the series-2 [[Thromboxane A2|thromboxanes]]<ref name="Piomelli" /> (TXA₂, TXB₂... ), each with two double bonds. Cyclooxygenase action on EPA (with 5 double bonds) leads to the series-3 thromboxanes (TXA₃, TXB₃, etc.), each with three double bonds. There are exceptions to this pattern, some of which indicate [[stereochemistry]] (PGF_2α).

==Eicosanoid series nomenclature==

: ''For details on the metabolic pathways for [[eicosanoid]]s in each series, see the main articles for [[prostaglandin]]s (PG), [[thromboxane]]s (TX), [[prostacyclin]]s (PGI) and [[leukotriene]]s (LK).

Table (1) shows these sequences for AA (20:4 ω-6). The sequences for [[eicosapentaenoic acid|EPA]] (20:5 ω-3) and [[dihomo-gamma-linolenic acid|DGLA]] (20:3 ω-6) are analogous.

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.

{| class="wikitable" style="margin:1em auto;"

[[Cell (biology)|Cell's]] outer [[Cell membrane|membranes]] contain [[phospholipid]] [[fat]]. Each phospholipid molecule contains two [[fatty acid]]s. Some of these fatty acids are 20-carbon [[PUFA|polyunsaturated]] essential fatty acids &ndash; 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. <ref name=Dorlands>{{cite web | title=Dorlands Medical Dictionary entry for 'Prostaglandin'| url=http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_p_36zPzhtm#1085994 | accessdate = October 23 | accessyear = 2005}}</ref> &nbsp; [[Cyclooxygenase]] (COX) oxidation removes two C=C [[Covalent bond|double bonds]], leading to the [[thromboxane|TX]], [[prostaglandin|PG]] and [[prostacyclin|PGI]] series.

|+Table 1 Three 20-carbon EFAs and the eicosanoid series derived from them

[[Lipoxygenase]] oxidation removes no C=C double bonds, and leads to the [[leukotriene|LK]]. <ref name=Cyberlipid>{{cite web|author=Cyberlipid Center| title= Polyenoic fatty acids| url= http://www.cyberlipid.org/fa/acid0003.htm | accessdate=February 11| accessyear=2006}}</ref>

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 [[arachidonic acid|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 &omega;-6). The sequences for [[eicosapentaenoic acid|EPA]] (20:5 &omega;-3) and [[dihomo-gamma-linolenic acid|DGLA]] (20:3 &omega;-6) are analogous.<center>

{| class="wikitable"

|+Table (1) Three 20-carbon EFAs and the eicosanoid series derived from them

|-

! rowspan=2|Dietary<br />Essential Fatty Acid

! rowspan=2|AbbrAbbreviation

! rowspan=2|Formula <br><font size=-2/>&omega; carbons: double bonds</font> ω

! colspan=3|Eicosanoid product series

|-

!TX<br />PG<br />PGI

!LK

!Effects

|-

|[[Gamma-linolenic acid]]<br />&nbsp;&nbsp; ''via'' [[Dihomo-gamma-linolenic acid|Dihomo gamma linolenic acid]]

|GLA<br />DGLA

| align=center|&omega;-6 18:33ω6<br />&omega;-6 20:33ω6

| series-1

| series-3

Line 41 ⟶ 36:

|[[Arachidonic acid]]

| AA

| align=center| &omega;-6 20:44ω6

| series-2

| series-4

| more inflammatory

|-

|[[Eicosapentaenoic acid]]

| EPA

| align=center| &omega;-3 20:55ω3

|series-3

| series-5

| less inflammatory

|-}

All prostanoids are substituted [[prostanoic acid]]s.

|}</center>

Cyberlipid Center's Prostenoid page<ref name=cyber2>{{cite web| author=Cyberlipid Center| title=Prostanoids| url=http://www.cyberlipid.org/prost1/pros0001.htm#9| access-date=February 11, 2006| archive-url=https://web.archive.org/web/20070208145938/http://www.cyberlipid.org/prost1/pros0001.htm#9| archive-date=February 8, 2007| url-status=dead}}</ref> illustrates the parent compound and the rings associated with each series letter.

All the prostenoids are substituted prostanoic acids.

Cyberlipid Center's Prostenoid page<ref name=cyber2>{{cite web|author=Cyberlipid Center| title=Prostanoids|url= http://www.cyberlipid.org/prost1/pros0001.htm#9 | accessdate=February 11| accessyear=2006}}</ref> illustrates the parent compound and the rings associated with each series&ndash;letter.

The [[International Union of Pure and Applied Chemistry|IUPAC]] and the [[International Union of Biochemistry and Molecular Biology|IUBMB]] use the equivalent term '''icosanoid'''.<ref name="cyber2" />

==Arachidonic acid cascade in inflammation==

[[Image:Eicosanoid_synthesis.svg|frame|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]] (18:2 &omega;-6) is lengthened and desaturated to form arachidonic acid, [[Ester|esterified]] into the [[phospholipid]] fats in the [[cell membrane]]. Next, in response to many inflammatory [[Stimulus (physiology)|stimuli]], [[phospholipase]] is generated and cleaves this fat, releasing AA as a [[Fatty acid|free fatty acid]]. AA can then be oxygenated and then further modified to form [[eicosanoid]]s &ndash; [[autocrine signalling|autocrine]] and [[paracrine signalling|paracrine agents]] that bind [[Receptor (biology)|receptors]] on the cell or its neighbors. Alternatively, AA can diffuse into the [[cell nucleus]] and interact with [[transcription factor]]s to control [[Transcription (genetics)|DNA transcription]] for [[cytokine]]s or other hormones.

== The arachidonic acid cascade in the Central Nervous System ==

===Mechanisms of &omega;-3 eicosanoid action===

{{quote box|quote=The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with.|source= Daniele Piomelli ''Arachidonic Acid''<ref name=Piomelli />|width=25%}}

[[Image:EFA_to_Eicosanoid.JPG|480px|right|thumb|Figure (2) Essential fatty acid production and metabolism to form Eicosanoids]]

The eicosanoids from AA generally promote inflammation. Those from [[Gamma-linolenic acid|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<ref name=Calder>{{cite web|author= Calder, Philip C. |year= September 2004 |title=n-3 Fatty Acids and Inflammation &ndash; New Twists in an Old Tale|accessdate=February 8|accessyear=2006| url=http://fatsoflife.com/articlePrint.asp?id=197}}

* Invited review article, PUFA Newsletter.</ref> or Tilley.<ref name=Tilley>{{cite journal |author=Tilley S, Coffman T, Koller B |title=Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes |journal=J Clin Invest |volume=108 |issue=1 |pages=15-23 |year=2001 |id=PMID 11435451|url=http://www.jci.org/cgi/reprint/108/1/15 |accessdate=2007-01-30}}</ref>)

The arachidonic acid cascade proceeds somewhat differently in the [[central nervous system]] (CNS). [[Neurohormone]]s, [[neuromodulator]]s, or [[neurotransmitter]]s act as first messengers. They activate phospholipids to release AA from [[neuron]] cell membranes as a free fatty acid.{{Citation needed|date=February 2020}} During its short lifespan, free AA may affect the activity of the neuron's [[ion channel]]s and [[protein kinase]]s. Or it may be metabolized to form eicosanoids, [[epoxyeicosatrienoic acid]]s (EETs), [[neuroprotectin]] D, or various [[Cannabinoid#Endogenous Cannabinoids|endocannabinoids]] ([[anandamide]] and its analogs).

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

The actions of eicosanoids within the brain are not as well characterized as they are in inflammation. Studies suggest that they act as [[Second messenger system|second messengers]] within the neuron, possibly controlling presynaptic inhibition and the activation of [[protein kinase]] C. They also act as paracrine mediators, acting across synapses to nearby cells. The effects of these signals are not well understood. [[Daniele Piomelli]] has commented:

Dietary &omega;-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways &ndash; displacement, [[Competitive inhibitor|competitive inhibition]] and direct counteraction.

<blockquote>

====Displacement====

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 that 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. Studies have proposed that arachidonic acid metabolites participate in retrograde signaling and other forms of local modulation of neuronal activity.<ref name=Piomelli/>

Dietary &omega;-3 decreases tissue concentrations of AA.

</blockquote>

Animal studies show that increased dietary &omega;-3 results in decreased AA in brain and other tissue, <ref name=Medical>{{cite web |author=Medical Study News| title=Brain fatty acid levels linked to depression |year= 25-May-2005 |accessdate= February 10|accessyear=2006|url= http://www.news-medical.net/?id=10398}}

{| class=wikitable style="margin: 1em 0 1em 1em;"

* Who were in turn citing {{cite web|title=Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression |author=Pnina Green, Iris Gispan-Herman and Gal Yadid| accessdate= February 10|accessyear=2006|url= http://www.jlr.org/cgi/content/abstract/46/6/1093|year=June 2005}}</ref>. [[Linolenic acid]] (18:3 &omega;-3) contributes to this by displacing [[linoleic acid]] (18:2 &omega;-6) from the elongase and [[desaturase]] enzymes that produce AA. EPA inhibits [[phospholipase]] A2's release of AA from cell membrane.<ref name=Su>{{cite web| author=KP Su, SY Huang, CC Chiu, WW Shen | url=http://nutri.tmu.edu.tw/slide/b2.pdf |title=Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled ?|year=2003 |accessdate= February 22|accessyear=2006}}</ref> &nbsp; Other mechanisms involving the transport of EFAs may also play a role.

|+ Table 2.The arachidonic acid cascades act differently between the inflammatory response and the brain.

The reverse is also true &ndash; high dietary linoleic acid decreases the body's conversion of &alpha;-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for &alpha;-linolenic acid than it has for linoleic acid, <ref name=Phinney>{{cite journal

| author=Phinney, SD , RS Odin, SB Johnson and RT Holman

| journal = American Journal of Clinical Nutrition

| volume = 51 | pages = 385-392

|title=Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans

|url=http://intl.ajcn.org/cgi/content/abstract/51/3/385

|accessdate=February 11|accessyear=2006|year=1990}}

* "[D]ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."</ref>.

==== 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. <ref name=Guivernau>{{cite web | author= Guivernau M, Meza N, Barja P, Roman O. |id=PMID 7846101|year=Nov 1994 |url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7846101&query_hl=2&itool=pubmed_docsum | title= ''Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production.'' |accessdate= 4 February |accessyear=2005}}

* GLA decreases triglycerides, LDL, increases HDL, decreases TXB₂ and other inflammatory markers. Review article; human and rat studies.</ref> <ref name=Karlstaad>{{cite web | title=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| year= Nov 1993 | url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8222692&query_hl=1&itool=pubmed_docsum | author= Karlstad MD, DeMichele SJ, Leathem WD, Peterson MB.| accessdate= February 6 |accessyear=2006}}

* IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB₂.</ref> Likewise, EPA inhibits the production of series-2 PG and TX. <ref name=Calder> Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs. <ref name=Belch>{{cite web| author= Belch, Jill JF and Alexander Hill| title=Evening primrose oil and borage oil in rheumatologic conditions|year=January 2000| url= http://www.ajcn.org/cgi/content/full/71/1/352S|accessdate=February 12|accessyear=2006}}

* "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."</ref>

==== Counteraction ====

Some DGLA and EPA derived eicosonoids counteract their AA derived counterparts. For example, DGLA yields PGE₁, which powerfully counteracts PGE₂. <ref name=Fan>{{cite journal | author=Fan, Yang-Yi and Robert S. Chapkin

| title=''Importance of Dietary gamma -Linolenic Acid in Human Health and Nutrition''

| url=http://jn.nutrition.org/cgi/content/full/128/9/1411

| year= 9 September 1998 | accessdate= 2007-01-05

| journal =Journal of Nutrition

| volume = 128 |issue = 9 |pages = 1411-1414}}

* "[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."</ref> &nbsp; EPA yields the antiaggregatory prostacyclin PGI₃ <ref name=Fischer>{{cite web | author = Fischer S, Weber PC| url= http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2996649&dopt=Citation |year= Sep 1985 | title = 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.| accessdate=February 10|accessyear=2006}}</ref> <!--Is this a good counteraction example?--> It also yields the leuokotriene LTB₅ which vitiates the action of the AA-derived LTB₄. <ref name=Prescott>{{cite web|author=Prescott, Scott|url= http://scholar.google.com/url?sa=U&q=http://www.jbc.org/cgi/reprint/259/12/7615.pdf | title= The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils. |year=1984|accessdate=February 16|accessyear=2006}}</ref>

===The paradox of dietary GLA===

Dietary [[linoleic acid]] (LA, 18:2 &omega;-6) is inflammatory. In the body, LA is desaturated to form GLA (18:3 &omega;-6). But dietary GLA is anti-inflammatory. How is this possible?

Some observations partially explain this paradox. LA competes with [[Alpha-linolenic acid|&alpha;-linolenic acid]], (ALA, 18:3 &omega;-3) for &Delta;6-desaturase, and thereby eventually inhibits formation of anti-inflammatory EPA (20:5 &omega;-3). In contrast, GLA does not compete for &Delta;6-desaturase. GLA's elongation product DGLA (20:3 &omega;-6) competes with 20:4 &omega;-3 for the &Delta;5-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 step|rate-determining]]. &Delta;6-desaturase does appear to be the rate-limiting step; 20:4 &omega;-3 does not significantly accumulate in bodily lipids.

DGLA inhibits inflammation through both competitive inhibition and direct counteraction (see [[#Inflammation effect|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.<ref name=Fan>

It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small.<ref name=Karlstaad> The empirical observation of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate, <ref name=Stone>{{cite web|author=Stone KJ, Willis AL, Hart WM, Kirtland SJ, Kernoff PB, McNicol GP.| year=1979 Feb|title=The metabolism of dihomo-gamma-linolenic acid in man.|accessdate=February 15|accessyear=2006|url= http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=423720&dopt=Citation}}</ref>.

===Complexity of pathways===

Eicosanoid signaling paths are complex.

It is therefor difficult to characterize the action any particular eicosanoid.

For example, PGE₂ binds four receptors, dubbed EP1&ndash;4.

Each is coded by a separate gene, and some exist in multiple [[isoform]]s.

Each EP receptor in turn couple to a [[G protein]].

EP₂, EP₄ and one isoform of the EP₃ receptors couple to G_s.

This increases intracellular [[Cyclic adenosine monophosphate|cAMP]] and is anti-inflammatory. EP₁ and other EP₃ isoforms couple to G_q.

This leads to increased intracellular calcium and is pro-inflammatory.

Finally, yet another EP₃ isoform couples to G_i, which both decreases cAMP and increases calcium. Many immune-system cells express multiple receptors that couple these apparently opposing pathways.<ref name=Tilley />

Presumably, EPA-derived PGE3 has a somewhat different effect of on this system, but it is not well-characterized.

==The arachidonic acid cascade in the central nervous system (CNS)==

{| class=wikitable

|+ Table (2) The arachidonic acid cascades act differently between the inflammatory response and the brain.

|-

! colspan=3|Arachidonic Acid Cascade

Line 140 ⟶ 82:

! Triggers for AA release

|Inflammatory stimuli

|Neurotransmitters, neurohormones<br /> and neuromodulators

|-

! Intracellular effects on

|DNA transcription of cytokines and other <br />mediators of inflammation

|Activity of ion channels and protein<br /> kinases

|-

! Metabolized to form

|Eicosanoids, resolvins, isofurans, isoprostanes,<br />lipoxins, epoxyeicosatrienoic acids (EETs)

|Eicosanoids, neuroprotectin D, EETs <br />and some endocannabinoids

|-

|}

== Further discussion ==

<blockquote>"The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with." &ndash; Piomelli, 2000</blockquote>

Figure 2 shows two pathways from EPA to [[Docosahexaenoic acid|DHA]], including the exceptional [[Docosahexaenoic acid#Metabolic synthesis|Sprecher's shunt]].

5-LO acts at the fifth carbon from the [[Carboxylic acid|carboxyl group]].

The arachidonic acid cascade proceeds somewhat differently in the brain. [[Neurohormone]]s, [[neuromodulator]]s or [[neurotransmitter]]s 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 channel]]s and [[protein kinase]]s. Or it may be metabolized to form eicosanoids, [[epoxyeicosatrienoic acid]]s (EETs), [[neuroprotectin]] D or various [[Cannabinoid#Endogenous Cannabinoids|endocannabinoids]] ([[anandamide]] and its analogs.)

Other lipoxygenases—8-LO, 12-LO, and 15-LO—make other eicosanoid-like products.

To act, 5-LO uses the nuclear-membrane [[enzyme]] [[5-Lipoxygenase activating protein|5-lipoxygenase-activating protein]] ('''FLAP'''), first to a [[hydroperoxyeicosatetraenoic acid]] ('''HPETE'''), then to the first leukotriene, LTA.

== See also ==

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 messenger]]s controlling presynaptic inhibition and the activation of [[Protein kinase|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

*[[Docosanoid]]

<blockquote>

*[[Eicosanoid]]

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&mdash;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.

*[[Essential fatty acid]]

</blockquote>

*[[Fatty acid ratio in food]]

== References ==

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.

{{Reflist|30em}}

[[Category:Docosanoids]]

==Further Discussion==

[[Category:Eicosanoids]]

Figure (2) shows one pathway from EPA to DHA; for an alternative, see [[Docosahexaenoic_acid#Metabolic_synthesis|Sprecher's shunt]].

[[Category:Fatty acids]]

[[Category:Immune system]]

[[ca:Àcids grassos essencials#Interacció d'àcids grassos essencials]]

== See Also ==

*[[Essential fatty acids]]

*[[Omega-3 fatty acids]]

*[[Omega-6 fatty acids]]

*[[List of omega-3 fatty acids]]

*[[Eicosanoids]]

==References==

<references />

[[Category:Fatty acids]]