Essential fatty acid interactions
Encyclopedia
The actions of the ω-3
(Omega-3) and ω-6
(Omega-6) essential fatty acids (EFAs) are best characterized by their interactions; they cannot be understood separately.
Arachidonic acid
(AA) is a 20-carbon ω-6 conditionally essential fatty acid. It sits at the head of the "arachidonic acid cascade" – more than twenty different signalling paths that control a wide array of bodily functions, but especially those functions involving inflammation
and the central nervous system
. Most AA in the human body derives from dietary linoleic acid
(another essential fatty acid, 18:2 ω-6), which comes both from vegetable oils and animal fat
s.
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 alpha-linolenic acid
found in, for instance, hemp oil
and 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.
Today, the usual diet in industrial countries contains much less ω-3 fatty acids than the diet of a century ago. The diet from a century ago had much less ω-3 than the diet of early hunter-gatherer
s,. We can also look at the ratio of ω-3 to ω-6 in comparisons of 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 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.
Eicosanoids are signalling molecules derived from the essential fatty acids (EFA); 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 acid
s. 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. 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
.
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. There are exceptions to this pattern, some of which indicate stereochemistry
(PGF2α).
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.
All the prostenoids are substituted prostanoic acids.
Cyberlipid Center's Prostenoid page illustrates the parent compound and the rings associated with each series–letter.
The IUPAC
and the IUBMB
use the equivalent term Icosanoid.
In the arachidonic acid cascade, dietary linoleic acid
(18:2 ω-6) is lengthened and desaturated to form arachidonic acid, ester
ified 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 eicosanoid
s – 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 factor
s to control DNA transcription
for cytokine
s or other hormones.
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 or Tilley.)
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.
Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue,. 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. Other mechanisms involving the transport of EFAs may also play a role.
The reverse is also 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,.
(LA, 18:2 ω-6) is inflammatory. 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 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, where LA does not. This may reflect white blood cells' lack of desaturase. Supplementing dietary GLA increases serum DGLA without increasing serum AA.
It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small. The empirical observation of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate.
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.
Presumably, EPA-derived PGE3 has a somewhat different effect of on this system, but it is not well-characterized.
s, neuromodulators 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 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
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.
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 leuokotriene, LTA.
Omega-3 fatty acid
N−3 fatty acids are essential unsaturated fatty acids with a double bond starting after the third carbon atom from the end of the carbon chain....
(Omega-3) and ω-6
Omega-6 fatty acid
n−6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−6 position, that is, the sixth bond, counting from the methyl end.The biological effects of the n−6 fatty acids are largely mediated by their conversion to n-6 eicosanoids...
(Omega-6) essential fatty acids (EFAs) are best characterized by their interactions; they cannot be understood separately.
Arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
(AA) is a 20-carbon ω-6 conditionally essential fatty acid. It sits at the head of the "arachidonic acid cascade" – more than twenty different signalling paths that control a wide array of bodily functions, but especially those functions involving inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Most AA in the human body derives from dietary linoleic acid
Linoleic acid
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
(another essential fatty acid, 18:2 ω-6), which comes both from vegetable oils and animal fat
Animal fat
Animal fats are rendered tissue fats that can be obtained from a variety of animals.- Pet nutrition :In pet nutrition, the source of animal fat concerns food manufacturers. AAFCO states that animal fat is "obtained from the tissues of mammals and/or poultry in the commercial processes of rendering...
s.
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)
Eicosapentaenoic acid
Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic acid...
provides the most important competing cascade. It is ingested from oily fish
Fish oil
Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid , and docosahexaenoic acid , precursors of certain eicosanoids that are known to reduce inflammation throughout the body, and are thought to have many health benefits.Fish do not...
or derived from dietary alpha-linolenic acid
Alpha-linolenic acid
α-Linolenic acid is an organic compound found in many common vegetable oils. In terms of its structure, it is named all-cis-9,12,15-octadecatrienoic acid. In physiological literature, it is given the name 18:3 ....
found in, for instance, hemp oil
Hemp oil
Hempseed oil is pressed from the seed of the hemp plant irrespective of the strain of cannabis. Cold pressed, unrefined hemp oil is dark to clear light green in color, with a pleasant nutty flavor. The darker the color, the grassier the flavour....
and flax oil
Flax
Flax is a member of the genus Linum in the family Linaceae. It is native to the region extending from the eastern Mediterranean to India and was probably first domesticated in the Fertile Crescent...
. DGLA (20:3 ω-6)
Dihomo-gamma-linolenic acid
Dihomo-γ-linolenic acid is a 20-carbon ω−6 fatty acid. In physiological literature, it is given the name 20:3 . DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end. DGLA is the elongation product...
provides a third, less prominent cascade. It derives from dietary GLA (18:3 ω-6)
Gamma-Linolenic acid
γ-Linolenic acid is a fatty acid found primarily in vegetable oils...
found in, e.g. borage oil
Borage
Borage, , also known as a starflower, is an annual herb originating in Syria, but naturalized throughout the Mediterranean region, as well as Asia Minor, Europe, North Africa, and South America. It grows to a height of , and is bristly or hairy all over the stems and leaves; the leaves are...
. 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.
Today, the usual diet in industrial countries contains much less ω-3 fatty acids than the diet of a century ago. The diet from a century ago had much less ω-3 than the diet of early hunter-gatherer
Hunter-gatherer
A hunter-gatherer or forage society is one in which most or all food is obtained from wild plants and animals, in contrast to agricultural societies which rely mainly on domesticated species. Hunting and gathering was the ancestral subsistence mode of Homo, and all modern humans were...
s,. We can also look at the ratio of ω-3 to ω-6 in comparisons of their diets. These changes have been accompanied by increased rates of many diseases – the so-called diseases of civilization
Lifestyle diseases
Lifestyle diseases are diseases that appear to increase in frequency as countries become more industrialized and people live longer...
– that involve inflammatory processes. There is now very strong evidence 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 eicosanoidEicosanoidIn biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s in each series, see the main articles for prostaglandinProstaglandinA prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s (PG), thromboxaneThromboxaneThromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
s (TX), prostacyclinProstacyclinProstacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
s (PGI) and leukotrieneLeukotrieneLeukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
s (LK).
Eicosanoids are signalling molecules derived from the essential fatty acids (EFA); 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
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
outer membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
contain phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
. Each phospholipid molecule contains two fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s. 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. Cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
(COX) oxidation removes two C=C double bonds
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
, leading to the TX
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
, PG
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
and PGI
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
series.
Lipoxygenase
Lipoxygenase
Lipoxygenases are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:...
oxidation removes no C=C double bonds, and leads to the LK
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
.
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
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
(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. There are exceptions to this pattern, some of which indicate stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
(PGF2α).
Figure (1) shows these sequences for AA (20:4 ω-6). The sequences for EPA
Eicosapentaenoic acid
Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic acid...
(20:5 ω-3) and DGLA
Dihomo-gamma-linolenic acid
Dihomo-γ-linolenic acid is a 20-carbon ω−6 fatty acid. In physiological literature, it is given the name 20:3 . DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end. DGLA is the elongation product...
(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 Gamma-Linolenic acid γ-Linolenic acid is a fatty acid found primarily in vegetable oils... via Dihomo gamma linolenic acid Dihomo-gamma-linolenic acid Dihomo-γ-linolenic acid is a 20-carbon ω−6 fatty acid. In physiological literature, it is given the name 20:3 . DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end. DGLA is the elongation product... |
GLA DGLA |
ω-6 18:3 ω-6 20:3 |
series-1 | series-3 | less inflammatory |
| Arachidonic acid Arachidonic acid Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,... |
AA | ω-6 20:4 | series-2 | series-4 | more inflammatory |
| Eicosapentaenoic acid Eicosapentaenoic acid Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic 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.
The IUPAC
International Union of Pure and Applied Chemistry
The International Union of Pure and Applied Chemistry is an international federation of National Adhering Organizations that represents chemists in individual countries. It is a member of the International Council for Science . The international headquarters of IUPAC is located in Zürich,...
and the IUBMB
International Union of Biochemistry and Molecular Biology
The International Union of Biochemistry and Molecular Biology is an international non-governmental organisation concerned with biochemistry and molecular biology...
use the equivalent term Icosanoid.
Arachidonic acid cascade in inflammation
Linoleic acid
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
(18:2 ω-6) is lengthened and desaturated to form arachidonic acid, ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
ified into the phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
fats in the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Next, in response to many inflammatory stimuli
Stimulus (physiology)
In physiology, a stimulus is a detectable change in the internal or external environment. The ability of an organism or organ to respond to external stimuli is called sensitivity....
, phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
is generated and cleaves this fat, releasing AA as a free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
. AA can then be oxygenated and then further modified to form eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s – autocrine
Autocrine signalling
Autocrine signaling is a form of signalling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on the same cell, leading to changes in the cell...
and paracrine agents
Paracrine signalling
Paracrine signalling is a form of cell signalling in which the target cell is near the signal-releasing cell.-Local action:Some signalling molecules degrade very quickly, limiting the scope of their effectiveness to the immediate surroundings...
that bind receptors on the cell or its neighbors. Alternatively, AA can diffuse into the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and interact with transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s to control DNA transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
for cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s or other hormones.
Mechanisms of ω-3 eicosanoid action
Gamma-Linolenic acid
γ-Linolenic acid is a fatty acid found primarily in vegetable oils...
(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 or Tilley.)
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,. Linolenic acid
Alpha-linolenic acid
α-Linolenic acid is an organic compound found in many common vegetable oils. In terms of its structure, it is named all-cis-9,12,15-octadecatrienoic acid. In physiological literature, it is given the name 18:3 ....
(18:3 ω-3) contributes to this by displacing linoleic acid
Linoleic acid
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
(18:2 ω-6) from the elongase and desaturase
Desaturase
A fatty acid desaturase is an enzyme that removes two hydrogen atoms from a fatty acid, creating a carbon/carbon double bond. These desaturases are classified as...
enzymes that produce AA. EPA inhibits phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
A2's release of AA from cell membrane. Other mechanisms involving the transport of EFAs may also play a role.
The reverse is also 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,.
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. Likewise, EPA inhibits the production of series-2 PG and TX. Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs.Counteraction
Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2. EPA yields the antiaggregatory prostacyclin PGI3 It also yields the leuokotriene LTB5 which vitiates the action of the AA-derived LTB4.The paradox of dietary GLA
Dietary linoleic acidLinoleic acid
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
(LA, 18:2 ω-6) is inflammatory. 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
Alpha-linolenic acid
α-Linolenic acid is an organic compound found in many common vegetable oils. In terms of its structure, it is named all-cis-9,12,15-octadecatrienoic acid. In physiological literature, it is given the name 18:3 ....
, (ALA, 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 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
Rate-determining step
The rate-determining step is a chemistry term for the slowest step in a chemical reaction. The rate-determining step is often compared to the neck of a funnel; the rate at which water flows through the funnel is determined by the width of the neck, not by the speed at which water is poured in. In...
. 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. Supplementing dietary GLA increases serum DGLA without increasing serum AA.
It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small. The empirical observation of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate.
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
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
.
The EP2, EP4 and one isoform of the EP3 receptors couple to Gs.
This increases intracellular cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
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.
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)
The arachidonic acid cascade proceeds somewhat differently in the brain. NeurohormoneNeurohormone
A neurohormone is any hormone produced and released by neurons.Examples include:*Thyrotropin-releasing hormone *Gonadotropin-releasing hormone *Adrenocorticotropin-releasing hormone*Oxytocin*Antidiuretic hormone *Epinephrine...
s, neuromodulators or neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s act as first messengers. They activate phospholipidase to release AA from neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
cell membranes as a free fatty acid. During its short lifespan, free AA may affect the activity of the neuron's ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s and protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s. Or it may be metabolized to form eicosanoids, epoxyeicosatrienoic acid
Epoxyeicosatrienoic acid
The Epoxyeicosatrienoic acids or EETs are signaling molecules formed by the action of Cytochrome P450 epoxygenase on 20-carbon essential fatty acids, such as arachidonic acid, from which it is produced by the enzyme epoxygenase....
s (EETs), neuroprotectin
Neuroprotectin
Neuroprotectin D1 is a docosanoid derived from the polyunsaturated fatty acid docosahexaenoic acid , which is a component of fish oil and the most important omega-3 PUFA. NPD1 exerts potent anti-inflammatory and anti-apoptotic bioactivity at nanomolar concentrations in a variety of experimental...
D or various endocannabinoids (anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
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
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
. 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 fluidInterstitial fluidInterstitial fluid is a solution that bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular 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.
| 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 ways in which these differently affect mental and neural processes are not nearly as well characterized as are the effects in inflammation.
Further discussion
Figure (2) shows one pathway from EPA to DHA; for an alternative, see Sprecher's shunt.5-LO acts at the fifth carbon from the carboxyl group
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
.
Other lipoxygenases—8-LO, 12-LO and 15-LO—make other eicosanoid-like products.
To act, 5-LO uses the nuclear-membrane enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
5-lipoxygenase-activating protein
5-lipoxygenase activating protein
Arachidonate 5-lipoxygenase-activating protein also known as 5-lipoxygenase activating protein, or FLAP, is a protein that in humans is encoded by the ALOX5AP gene.- Function :...
(FLAP), first to a hydroperoxyeicosatetraenoic acid (HPETE), then to the first leuokotriene, LTA.
See also
- Essential fatty acidEssential fatty acidEssential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them...
- Omega-3 fatty acidOmega-3 fatty acidN−3 fatty acids are essential unsaturated fatty acids with a double bond starting after the third carbon atom from the end of the carbon chain....
- Omega-6 fatty acidOmega-6 fatty acidn−6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−6 position, that is, the sixth bond, counting from the methyl end.The biological effects of the n−6 fatty acids are largely mediated by their conversion to n-6 eicosanoids...
- EicosanoidEicosanoidIn biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
- DocosanoidDocosanoidIn biochemistry, Docosanoids are signaling molecules made by oxygenation of twenty-two-carbon essential fatty acids, , especially Docosahexaenoic acid...