Essential fatty acid interactions

Source: Wikipedia, the free encyclopedia.
For introductory details to this topic, including terminology and ω-3 / ω-6 nomenclature, see Essential fatty acid and Eicosanoid.
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.

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,

eicosanoids
made from AA.

The diet from a century ago had much less ω-3 than the diet of early

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

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

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
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

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.

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

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

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

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

5-lipoxygenase-activating protein (FLAP), first to a hydroperoxyeicosatetraenoic acid
(HPETE), then to the first leukotriene, LTA.

See also

References

  1. PMID 14559071
    .
  2. PMID 34776851
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  3. ^ a b c Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress. Archived from the original on 2006-07-15. Retrieved 2006-03-03.
  4. ISSN 1874-2947.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link
    )
  5. S2CID 40659630
    .
  6. PMID 29156608
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  7. PMID 11935953. Archived from the original (PDF) on 2006-09-26. {{cite book}}: |journal= ignored (help
    )
  8. ^ National Institute of Health (2005-08-01). "Omega-3 fatty acids, fish oil, alpha-linolenic acid". Archived from the original on February 8, 2006. Retrieved August 21, 2010.
  9. doi:10.1016/S1520-765X(01)90118-X
    .
  10. ^ Cyberlipid Center. "Polyenoic fatty acids". Archived from the original on September 30, 2018. Retrieved February 11, 2006.
  11. ^ a b Cyberlipid Center. "Prostanoids". Archived from the original on February 8, 2007. Retrieved February 11, 2006.
  12. PMID 23674797
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  13. ^ a b Calder, Philip C. (September 2004). "n-3 Fatty Acids and Inflammation – New Twists in an Old Tale". Archived from the original on March 16, 2006. Retrieved February 8, 2006.
    • Invited review article, PUFA Newsletter.
  14. ^
    PMID 11435451
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  15. ^ Medical Study News (25 May 2005). "Brain fatty acid levels linked to depression". Retrieved February 10, 2006.
  16. ^ KP Su; SY Huang; CC Chiu; WW Shen (2003). "Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled?" (PDF). Archived from the original (PDF) on February 8, 2005. Retrieved February 22, 2006.
  17. PMID 2106775. Archived from the original
    on February 12, 2007. 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. PMID 7846101
    .
    • GLA decreases triglycerides, LDL, increases HDL, decreases TXB2 and other inflammatory markers. Review article; human and rat studies.
  19. ^
    S2CID 36538810
    .
    • IV Supplementation with gamma-linolenic acid increased serum GLA but did not increase the plasma percentage of arachidonic acid (rat study), decreased TXB2.
  20. 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. ^
    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. PMID 2996649
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  23. PMID 6330066
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  24. PMID 9237935
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  25. S2CID 41372225
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