Biology:Essential fatty acid interactions

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Fatty Acid breakdown
Fatty acid breakdown

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

Arachidonic acid (AA) is a 20-carbon omega-6 essential fatty acid.[1] It sits at the head of the "arachidonic acid cascade," which initiates 20 different signalling pathways that control a wide array of biological functions, including inflammation, cell growth, and the central nervous system.[2][3] Most AA in the human body is derived from dietary linoleic acid (18:2 ω-6), which is found in nuts, seeds, vegetable oils, and animal fats.[4][5][6]

Other dietary essential fatty acids are involved in inflammatory signalling and can oppose the impact of the arachidonic acid cascade. For example, EPA (20:5 ω-3) competes with AA and is ingested from oily fish, algae oil, or alpha-linolenic acid (derived from walnuts, hemp oil, and flax oil). Another example is DGLA (20:3 ω-6), derived from dietary GLA (18:3 ω-6), is found in borage oil and can also. These two parallel cascades soften the inflammatory-promoting effects of specific eicosanoids made from AA.

The diet from a century ago had much less ω-3 than the diet of early hunter-gatherers but also much less pollution than today,[7] which evokes the inflammatory response. We can also look at the ratio of ω-3 to ω-6 in comparison with their diets. These changes have been accompanied by increased rates of many diseases—the so-called diseases of civilization—that involve inflammatory processes. There is now very strong evidence[8] that several of these diseases are ameliorated by increasing dietary ω-3. There is also more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.[9]

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 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 plasma membranes of cells contain phospholipids, composed of a hydrophilic phosphate head and two hydrophobic fatty acid tails. Some of these fatty acids are 20-carbon polyunsaturated essential fatty acids (AA, EPA, or DGLA).[citation needed] In response to various 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) and further modified, yielding the eicosanoids.[citation needed] 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.[10]

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 AA (with 4 double bonds) leads to the series-2 thromboxanes[3] (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 (PGF2α).

Table (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.

Table 1 Three 20-carbon EFAs and the eicosanoid series derived from them
Dietary
Essential Fatty Acid 		Abbreviation Formula
carbons:double bonds ω 		Eicosanoid product series
TX
PG
PGI 		LK Effects
Gamma-linolenic acid
   via Dihomo gamma linolenic acid 		GLA
DGLA 		18:3ω6
20:3ω6 		series-1 series-3 less inflammatory
Arachidonic acid AA 20:4ω6 series-2 series-4 more inflammatory
Eicosapentaenoic acid EPA 20:5ω3 series-3 series-5 less inflammatory

All prostanoids are substituted prostanoic acids. Cyberlipid Center's Prostenoid page[11] illustrates the parent compound and the rings associated with each series letter.

The IUPAC and the IUBMB use the equivalent term icosanoid.[11]

Arachidonic acid cascade in inflammation

Figure (1) The Arachidonic acid cascade, showing biosynthesis of AA's eicosanoid products. EPA 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 ω-6) is desaturated and elongated to form arachidonic acid (and other omega-6 acids), which is then esterified into a phospholipid in the cell membrane.[12] Next, in response to many inflammatory stimuli, such as air pollution, smoking, second-hand smoke, hydrogenated vegetable oils, and other exogenous toxins, phospholipase is generated and cleaves this phospholipid, releasing AA as a free fatty acid.[citation needed] 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 to alert the immune system of cell damage. 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

Figure 2. Essential fatty acid production and metabolism to form eicosanoids

Eicosanoids from AA have been found to promote inflammation. Those from GLA (via DGLA) and from EPA are generally less inflammatory, inactive, or 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[13] or Tilley.[14])

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 decreases AA in the brain and other tissues.[15] alpha-Linolenic acid (18:3 ω-3) contributes 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 the cell membrane.[16]  Other mechanisms involving the transport of EFAs may also play a role.

The reverse is true: high dietary linoleic acid 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 has for linoleic acid.[17]

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 eicosanoids. For example, dietary GLA increases tissue DGLA and lowers TXB2.[18][19] Likewise, EPA inhibits the production of series-2 PG and TX.[13] Although DGLA does not form LTs, a DGLA derivative blocks the transformation of AA to LTs.[20]

Counteraction

Some DGLA and EPA-derived eicosanoids counteract their AA-derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2.[21]  EPA yields the antiaggregatory prostacyclin PGI3 [22]. It also yields the leukotriene LTB5, which vitiates the action of the AA-derived LTB4.[23]

The paradox of dietary GLA

Studies have shown that dietary oxidized linoleic acid (LA, 18:2 ω-6) has inflammatory properties. In the body, LA is desaturated to form GLA (18:3 ω-6), yet dietary GLA is anti-inflammatory. Some observations partially explain this paradox: LA competes with α-linolenic acid (ALA, 18:3 ω-3) for Δ6-desaturase and thereby eventually inhibits the formation of anti-inflammatory EPA (20:5 ω-3). In contrast, GLA does not compete 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, 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, whereas LA does not. This may reflect white blood cells' lack of desaturase. Supplementing dietary GLA increases serum DGLA without increasing serum AA.[21][24]

It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small.[19] The empirical observation of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate.[25]

Complexity of pathways

Eicosanoid signaling paths are complex. It is therefore difficult to characterize the action of any particular eicosanoid. For example, PGE2 binds four receptors, dubbed EP1–4. Each is coded by a separate gene, and some exist in multiple isoforms. Each EP receptor, in turn, couples to a G protein. The EP2, EP4, and one isoform of the EP3 receptors couple to Gs. This increases intracellular cAMP and is anti-inflammatory. EP1 and other EP3 isoforms couple to Gq. This leads to increased intracellular calcium and is pro-inflammatory. Finally, yet another EP3 isoform couples to Gi, which both decreases cAMP and increases calcium. Many immune system cells express multiple receptors that couple these apparently opposing pathways.[14] Presumably, EPA-derived PGE3 has a somewhat different effect on this system, but it is not well characterized.

The arachidonic acid cascade in the Central Nervous System (CNS)

The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with.

Daniele Piomelli Arachidonic Acid[3]

The arachidonic acid cascade proceeds somewhat differently in the brain. Neurohormones, neuromodulators, or neurotransmitters act as first messengers. They activate phospholipids to release AA from neuron cell membranes as a free fatty acid.[citation needed] 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. Studies suggest that they act as 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. (Piomelli, 2000) states that there is little information available.

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.

Table 2.The arachidonic acid cascades act differently between the inflammatory response and the brain.
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 neuromodulators
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 EPA and DGLA cascades are also present in the brain, and their eicosanoid metabolites have been detected. The effects of EPA and DGLA cascades on mental and neural processes are not as well characterized as their effects on inflammation.

Further discussion

Figure 2 shows two pathways from EPA to DHA, including the exceptional Sprecher's shunt.

5-LO acts at the fifth carbon from the carboxyl group. 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 (FLAP), first to a hydroperoxyeicosatetraenoic acid (HPETE), then to the first leukotriene, LTA.

See also

References

  1. ↑ "Problems with essential fatty acids: time for a new paradigm?". Progress in Lipid Research 42 (6): 544–568. November 2003. doi:10.1016/S0163-7827(03)00038-9. PMID 14559071. 
  2. ↑ "Quality of Life and a Surveillant Endocannabinoid System". Frontiers in Neuroscience 15: 747229. 2021. doi:10.3389/fnins.2021.747229. PMID 34776851. 
  3. ↑ 3.0 3.1 3.2 Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress. http://www.acnp.org/g4/GN401000059/Default.htm. 
  4. ↑ "Chlorella vulgaris as a Source of Essential Fatty Acids and Micronutrients: A Brief Commentary". The Open Plant Science Journal 10 (1): 92–99. 2017-08-25. doi:10.2174/1874294701710010092. ISSN 1874-2947. 
  5. ↑ "Polyunsaturated fatty acids and endocannabinoids in health and disease". Nutritional Neuroscience 21 (10): 695–714. December 2018. doi:10.1080/1028415X.2017.1347373. PMID 28686542. 
  6. ↑ "Fatty Acids, Antioxidants and Physical Activity in Brain Aging". Nutrients 9 (11): 1263. November 2017. doi:10.3390/nu9111263. PMID 29156608. 
  7. ↑ Simopoulos A (2001). "Evolutionary aspects of diet and essential fatty acids". Fatty Acids and Lipids – New Findings. World Review of Nutrition and Dietetics. 88. 18–27. doi:10.1159/000059742. ISBN 978-3-8055-7182-1. http://eurheartjsupp.oxfordjournals.org/cgi/reprint/3/suppl_D/D8.pdf. 
  8. ↑ National Institute of Health (2005-08-01). "Omega-3 fatty acids, fish oil, alpha-linolenic acid". https://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-fishoil.html. 
  9. ↑ "n-3 Fatty acids and the inflammatory response — biological background". European Heart Journal Supplements 3 (suppl D): D42–D49. 2001. doi:10.1016/S1520-765X(01)90118-X. 
  10. ↑ Cyberlipid Center. "Polyenoic fatty acids". http://www.cyberlipid.org/fa/acid0003.htm. 
  11. ↑ 11.0 11.1 Cyberlipid Center. "Prostanoids". http://www.cyberlipid.org/prost1/pros0001.htm#9. 
  12. ↑ "Linoleic acid". Advances in Nutrition 4 (3): 311–312. May 2013. doi:10.3945/an.113.003772. PMID 23674797. 
  13. ↑ 13.0 13.1 Calder, Philip C. (September 2004). "n-3 Fatty Acids and Inflammation – New Twists in an Old Tale". http://fatsoflife.com/articlePrint.asp?id=197. 
    • Invited review article, PUFA Newsletter.
  14. ↑ 14.0 14.1 "Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes". The Journal of Clinical Investigation 108 (1): 15–23. July 2001. doi:10.1172/JCI13416. PMID 11435451. 
  15. ↑ Medical Study News (25 May 2005). "Brain fatty acid levels linked to depression". http://www.news-medical.net/?id=10398. 
    • Who were in turn citing "Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression". Journal of Lipid Research 46 (6): 1093–1096. June 2005. doi:10.1194/jlr.C500003-JLR200. PMID 15805551. 
  16. ↑ "Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled?". 2003. http://nutri.tmu.edu.tw/slide/b2.pdf. 
  17. ↑ "Reduced arachidonate in serum phospholipids and cholesteryl esters associated with vegetarian diets in humans". The American Journal of Clinical Nutrition 51 (3): 385–392. March 1990. doi:10.1093/ajcn/51.3.385. PMID 2106775. http://intl.ajcn.org/cgi/content/abstract/51/3/385. Retrieved February 11, 2006. 
    • "[D]ietary arachidonic acid enriches its circulating pool in humans; however, 20:5n-3 is not similarly responsive to dietary restriction."
  18. ↑ "Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production". Prostaglandins, Leukotrienes, and Essential Fatty Acids 51 (5): 311–316. November 1994. doi:10.1016/0952-3278(94)90002-7. PMID 7846101. 
    • GLA decreases triglycerides, LDL, increases HDL, decreases TXB2 and other inflammatory markers. Review article; human and rat studies.
  19. ↑ 19.0 19.1 "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". Critical Care Medicine 21 (11): 1740–1749. November 1993. doi:10.1097/00003246-199311000-00025. PMID 8222692. 
    • IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB2.
  20. ↑ "Evening primrose oil and borage oil in rheumatologic conditions". The American Journal of Clinical Nutrition 71 (1 Suppl): 352S–356S. January 2000. doi:10.1093/ajcn/71.1.352s. PMID 10617996. 
    • "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."
  21. ↑ 21.0 21.1 "Importance of dietary gamma-linolenic acid in human health and nutrition". The Journal of Nutrition 128 (9): 1411–1414. September 1998. doi:10.1093/jn/128.9.1411. PMID 9732298. 
    • "[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."
  22. ↑ "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". Biomedical Mass Spectrometry 12 (9): 470–476. September 1985. doi:10.1002/bms.1200120905. PMID 2996649. 
  23. ↑ "The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils". The Journal of Biological Chemistry 259 (12): 7615–7621. June 1984. doi:10.1016/S0021-9258(17)42835-3. PMID 6330066. 
  24. ↑ "Dietary supplementation with gamma-linolenic acid alters fatty acid content and eicosanoid production in healthy humans". The Journal of Nutrition 127 (8): 1435–1444. August 1997. doi:10.1093/jn/127.8.1435. PMID 9237935. 
  25. ↑ "The metabolism of dihomo-gamma-linolenic acid in man". Lipids 14 (2): 174–180. February 1979. doi:10.1007/BF02533869. PMID 423720. 

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