A Look at Essential Fatty Acids

Celiac.com 10/15/2021 - Two infants born with short bowel syndrome and being sustained intravenously with parenteral nutrition develop life-threatening liver disease.  Cholestasis (blockage of bile secretion in the liver) places one infant on the liver transplantation list and threatens the other infant.  Miraculously, the liver disease is completely reversed in one infant and the other infant is taken off the transplantation list when the conventional soy-based intravenous fat emulsion formula is switched to a European formula containing mainly omega-3 essential fatty acids from fish oil(1).

A 10-year-old girl suffering from cholestasis, fat malabsorption, growth failure, and essential fatty acid deficiency is treated by long-term administration of essential fatty acids, mostly by the application of sunflower seed oil to the skin.  A remarkable growth catch-up occurs over several years and her essential fatty acid serum levels improve(2).

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A 31-year old man suffering from schizophrenia since his early teenage years experiences delusions, auditory hallucinations, social anxiety and withdrawal.  He refuses and remains free of antipsychotic medication.  In a research study, he consents to treatment with a daily dose of 2 grams of the omega-3 fatty acid eicosapentaenoic acid (EPA).  Over the course of just 6 months, he experiences a dramatic and sustained remission of symptoms.  Earlier nonpharmacological treatment had produced no benefit.  EPA, being the sole treatment he receives at the time, offers the only explanation for the remission(3).

In South Australia, an Adelaide study sets out to determine whether a combination of omega-3 fatty acids and regular exercise can reduce cardiovascular and metabolic risk factors better than either treatment alone in overweight people.  Participants are randomly given daily doses of either tuna fish oil, containing omega-3 fatty acids, or sunflower oil, containing no omega-3, without otherwise altering their diets and with or without exercise consisting of 45 minute walks 3 times a week.  After 3 months, the researchers are surprised to find the group receiving both exercise and fish oil and no change in diet unexpectedly loses an average of 5% body fat or 2kg.  All other groups lose no weight at all(4).

Studies and stories of the benefits of essential fatty acids, especially omega-3 fatty acids, seem to make the news almost daily.  There is a long and growing list of health conditions for which omega-3 and omega-6 fatty acids may play a role in preventing or reducing symptoms.  These conditions include cardiovascular disease, cancer, rheumatoid arthritis, inflammatory bowel disease, eczema, psoriasis, asthma, lupus erythematosus, multiple sclerosis, diabetes, schizophrenia, depression, autism, ADHD, Alzheimer's disease, retinitis pigmentosa, macular degeneration, osteoporosis, fibromyalgia, chronic fatigue syndrome, and more.  Often, though, reviews of such research studies find the data is inconclusive and that the studies need to be larger and better designed.  There is little profit incentive for pharmaceutical companies to fund well designed studies of essential fatty acids which are readily available from diet, so the data is likely to remain inconclusive for quite some time barring government and foundation funding.  Still, no one can deny the preponderance of evidence continually being added demonstrating health benefits from essential fatty acids.  The bottom line is, omega-3 and omega-6 fatty acids are, indeed, essential.

Omega-3 and omega-6 fatty acids are "essential" by definition because they cannot be produced by the human body and must be obtained from dietary sources.  The typical modern Western diet is usually high in omega-6 and low in omega-3 fatty acids.  Hence, scientists are most concerned about low levels of omega-3 fatty acids.  Deficiencies of omega-6 can also exist and cause problems.  Many vegetable oils, such as soy, are rich in omega-6.  A few vegetable oils, such as flaxseed and canola oils, have a high omega-3 content, but the most usable forms of omega-3 fatty acids come from cold water fish such as salmon.

Essential fatty acids combine with phosphate and glycerol to form phospholipids, a major component of all cell membranes, and, thus, play a prominent role in the activities and functions of cell membranes everywhere in the body(5).  Much of the health benefit of essential fatty acids comes from their role as precursors of an important group of bioactive regulatory compounds called prostaglandins.  Prostaglandins regulate numerous body states and functions.  An important role is played by prostaglandins in healing and protecting the body and its organs in response to injury from wounds, infection, and harmful chemicals.  Prostaglandins both promote and reduce inflammation.  Omega-3 and omega-6 fatty acids are converted into 3 different series of prostaglandins, PG1, PG2 and PG3.  Within each series, prostaglandins are designated by the letters A currently through K according to chemical structure.  The E prostaglandins, PGE1, PGE2, PGE3, are of special interest.  PGE1 and PGE3 are anti-inflammatory.  PGE2 is pro-inflammatory.  PGE1 and PGE2 are formed from omega-6 fatty acids.  Omega-3 fatty acids, in addition to forming PGE3, inhibit PGE2 production and encourage PGE1 production, and, therefore, omega-3 fatty acids are important in reducing inflammation.  

Prostaglandin D2 (PGD2), produced from omega-6 fatty acids, is secreted by mast cells along with histamine in response to allergens and may be involved in allergic inflammation in allergic diseases and food allergy.  Omega-3 fatty acids inhibit generation of PGD2 as well as PGE2.  Therefore, a diet rich in omega-3 fatty acids may reduce the severity of allergic reactions(6-8).

Significant amounts of lipids including fatty acids are found in the structure of hair, nails, and skin(9-12).  Thus, it is not surprising that an extreme deficiency of essential fatty acids can lead to scaly, blood oozing, dermatitis and inflammation of the hair follicles in the scalp as well as growth retardation and impaired wound healing(13-15).  An excessive amount of prostaglandin, PGE2, in the kidneys can lead to excessive urination and excretion of sodium.  A deficiency of omega-3 fatty acids may allow overproduction of PGE2 in the kidneys, thus, causing excessive urination(16-19).  Seven signs of fatty acid or lipid deficiency have been established.  These are:

• Dry skin
• Dry hair 
• Dandruff 
• Brittle nails 
• Excessive thirst 
• Frequent urination 
• Permanent goose bumps

When levels of omega-3 and omega-6 fatty acids are plentiful, they are readily stored in adipose or fatty tissue along with other fatty acids(20).

Fatty Acids and Celiac Disease

Celiac disease is a malabsorption disease which prominently includes fat malabsorption likely inhibiting intake of essential fatty acids. Steatorrhea, the formation of floating, oily, bulky, grey or light colored stools with a high fat content, is one of the most common symptoms of active celiac disease.  Yet there is almost no research concerning low or deficient levels of essential fatty acids associated with celiac disease.  What is more, sufficient supplies of vitamins C, E, B3, B6, B12, folic acid, iron, zinc and magnesium are required to maintain the process of converting essential fatty acids to prostaglandins and phospholipids(21-29).  A deficiency of these nutrients resulting from celiac disease, as well as essential fatty acid deficiency, could compromise or alter prostaglandin and phospholipid production and could contribute to growth retardation symptomatic of celiac disease in children in addition to numerous other medical conditions and immune disorders.  Celiac disease studies have looked at fecal fat content, cholesterol levels, and serum concentrations of plant sterols(30-31).  More interesting is that studies have found increased levels of PGE2 in the small intestinal mucosa of both children and adults with active celiac disease(32-33). 

A very recent and limited study looked at essential fatty acid levels in the serum and intestinal mucosa of pediatric patients.  The study included 7 pediatric patients with active celiac disease, 6 with celiac disease in remission, and 11 healthy controls.  Serum levels of fatty acids were similar between celiac disease patients and control patients, but abnormal omega-6 fatty acid levels were found in intestinal mucosa tissue samples from active celiac disease patients.  The results suggested an omega-6 fatty acid deficiency.  Omega-3 levels did not significantly differ.  This is not too surprising since PGE2 production from omega-6 fatty acids is increased in the intestines of active CD patients depleting available omega-6.  It should be noted that fatty acid profiles may prove to be different in adult celiac disease patients.  Also while omega-6 fatty acids may be deficient, increasing intake of omega-3 fatty acids may help reduce inflammatory processes in celiac disease(34).

Prostaglandins enhance mucosal repair and have a role in maintaining the paracellular pathway of the intestinal barrier.  The paracellular pathway involves the movement of ions and nutrients through the intercellular spaces between epithelial cells.  The gatekeeper of the paracellular pathway is the tight junction which permits the passage of ions and nutrients while restricting the movement of large molecules.  PGE2 in combination with PGI2 acts to increase tight junction closure, reducing intestinal permeability(35-36).  PGE1 has been shown to be active in healing the intestinal mucosa and reducing inflammation after damage occurs(37-41).  In Crohn's disease, an inflammatory bowel condition, omega-3 fatty acids have been shown to inhibit an increase of pro-inflammatory cytokines and are effective in maintaining remission of the disease(42-45).  Essential fatty acids might have similar beneficial effects in celiac disease. 

There is some experimental evidence suggesting prostaglandins may have a role in preventing villous atrophy due to food sensitivity, and that may include gluten.  Mice genetically engineered to be T cell responsive to a specific peptide of a hen egg protein displayed little reaction when fed the hen egg protein alone.  However,  when the mice were treated with a cyclooxygenase (COX) inhibitor, indomethacin, and then fed the hen egg protein, villous atrophy very similar to that experienced in celiac disease developed(46).  COX is an enzyme which converts omega-3 and omega-6 fatty acids to prostaglandins.  Inhibiting COX blocks prostaglandin production.  In another study, researchers found a positive expression of COX-2 in intestinal epithelial cells of active celiac disease patients(47).  COX-2 is a form of cyclooxygenase that generally only appears in tissues experiencing inflammation.  The exact role of COX-2 in celiac disease is unknown, but prostaglandin production resulting from COX-2 expression could have a protective or healing function.  This implies a role for essential fatty acids in celiac disease.  Could an inadequate diet, i.e. a dietary deficiency or imbalance of essential fatty acids, initially cause a breakdown of intestinal integrity and contribute to the onset of celiac disease itself?

Various lymphomas and cancers have been associated with celiac disease(48).  COX-2 is found to be expressed in lymphomas(49).  In a study, the omega-3 fatty acid, eicosapentaenoic acid (EPA), was added to a human lung cancer cell culture.  EPA inhibited PGE2 formation from COX-2 enzyme activity, instead using up COX-2 to form PGE3.  In turn, PGE3 inhibited the proliferation of the human lung cancer cells(50).  Another experiment with omega-3 fatty acids showed a similar supression of proliferation in mouse myeloma cells(51).  Hence, celiac disease caused omega-3 fatty acid deficiency might be associated with an increased lymphoma risk.

Liver damage is highly prevalent in celiac disease(52).  The liver damage may be the result of increased intestinal permeability in celiac disease which allows an increased amount of bacterial endotoxins from the gut to reach the liver.  The endotoxins initiate a cascade of inflammation in the liver resulting in liver damage(53).  Prostaglandins play roles in both protecting and regenerating the liver.  PGE1 has been demonstrated to be protective in cases of hepatitis and other chronic liver conditions(54).  Another study has shown PGE2 must be present for liver regeneration to proceed(55).  Thus, prostaglandins produced from essential fatty acids may ameliorate both the liver damage and the increased intestinal permeability which causes liver damage in celiac disease.

If essential fatty acids are so important to maintain health and intestinal integrity in celiac disease, then fat malabsorption presents a bit of a paradox by preventing absorption of the very nutrients needed to remedy the malabsorption.  Once a gluten-free diet is commenced, it would seem prudent to include in the diet plenty of essential fatty acids or fatty acid supplements, especially omega-3 fatty acids, to speed recovery.  Hopefully, the intestinal mucosa is sufficiently undamaged so that fat absorption is adequate.  But what if the mucosal damage is so severe that insufficient levels of fatty acids are absorbed compromising the ability of the intestine to heal itself due to inadequate prostaglandin production and resulting inflammation?  Could this be a factor in refractory sprue?  Does the intestine fail to heal because it can never absorb the essential fatty acids it needs to heal?  Could intravenous administration of a proper mix of emulsified omega-3 and omega-6 fatty acids help to alleviate refractory sprue?  There are a number of documented case studies in which external application of vegetable oils to the skin has been successful in raising levels of essential fatty acids in cases where deficiency has resulted from fat malabsorption or parenteral nutrition(56-59).  Could external application of oils containing essential fatty acids be useful to raise levels in refractory sprue or in severe cases of celiac disease?  These are intriguing questions.

The Chemistry of Fatty Acids

Essential fatty acids exist in omega-3 and omega-6 families of short to long chain fatty acids which vary in number of carbon and hydrogen atoms  represented by a chemical nomenclature.  Familiarity with this chemical nomenclature is necessary for looking up fat content in foods by searching the USDA National Nutrient Database.  Humans must at least include alpha-linolenic acid and linoleic acid in their diet.   These 2 fatty acids are, respectively, converted to all the other longer chain omega-3 and omega-6 fatty acids.

Prostaglandins are members of the eicosanoid family.  Eicosanoids are molecules generated from the 20-carbon-atom fatty acids (DGLA, AA, EPA) .

A full description of the omega-3, omega-6, and eicosanoidal conversion pathways and a link to the USDA database is provided in the Appendix below.

Mediators of Inflammation

As mentioned earlier, the pro- and anti-inflammatory properties of prostaglandins produced from essential fatty acids are key to the benefits of consuming an adequate diet of omega-3 and omega-6 fatty acids in the proper ratio.  

While inflammatory responses are important for our bodies to fight infections and help to heal injuries, too much and inappropriate inflammation is damaging to our health.  Eicosanoids derived from omega-6 fatty acid, arachidonic acid (AA), generally promote inflammation.  Eicosanoids derived from omega-6 fatty acid, dihomogamma-linolenic acid (DGLA), and from omega-3 fatty acid, eicosapentaenoic acid (EPA), counter inflammation.  Therefore, to reduce inflammation, it is desirable to inhibit the AA series 2 pathway and encourage the DGLA and EPA series 1 and 3 pathways.  Since DGLA can either be converted to AA or to series 1 prostaglandins, we want to prevent DGLA conversion to AA.  It just so happens that increasing intake of EPA has the ability to accomplish exactly what we want.  EPA inhibits the delta-5-desaturase conversion of DGLA to AA.  Additionally, increased EPA competes with AA for use of available cyclooxygenase (COX) to form series 3 prostaglandins, such as PGE3, thereby decreasing the COX formation of series 2 prostaglandins from AA, such as PGD2 and PGE2.  Hence, increased consumption of EPA has the potential to reduce inflammation in inflammatory diseases and health conditions(66-67).

Pain relieving drugs known as NSAIDS (nonsteroidal anti-inflammatory drugs) are COX inhibitors, relieving pain by inhibiting production of PGE2 to reduce inflammation.  Examples include aspirin, indomethacin (Indocin), ibuprofen (Advil, Motrin), naproxen (Aleve), piroxicam (Feldene), and naburnetone (Relafen).  COX exists in two forms, COX-1 and COX-2.  COX-1 is generally always present in all tissues throughout the body.  COX-2 is generally only expressed in tissues experiencing injury and inflammation.  The NSAIDs listed above block both COX-1 and COX-2.  This obviously interferes with eicosanoidal pathways.  As mentioned earlier, prostaglandins are necessary to maintain the integrity of the intestinal mucosa.  In normal tissues not experiencing inflammation, COX-1 maintains prostaglandin production.  If both COX-1 and COX-2 are inhibited in long term use of NSAIDs, the intestinal mucosa begins to suffer damage.  Newer NSAIDs such as celecoxib (Celebrex) and the now banned Vioxx and Bextra only inhibit COX-2, thereby blocking prostaglandin production only in inflamed tissues and reducing possible gastrointestinal injury.  (Celebrex still has cardiovascular and side-effect risk.)  Increasing consumption of EPA, over time (generally after at least several weeks of daily supplementation), can replace or complement the anti-inflammatory activity of NSAIDs.  EPA has no side-effects and is a much healthier option for relief of chronic pain due to inflammation.  NSAIDs could certainly aggravate the intestinal inflammation and damage already present in active celiac disease(68-71).

Trans fats have been a health issue of recent interest.  Trans fats are partially hydrogenated fats.  Commercial partially hydrogenated vegetable oils manufactured under pressure form semi-solid trans fats used to create margarine and shortening with long shelf-life replacing animal fats used in baked goods, fried foods, and snack foods.  Trans fats also occur naturally in small amounts in meat and dairy products.  Evidence suggests trans fats raise "bad" LDL cholesterol levels and lower "good" HDL levels leading to cardiovascular disease.  The FDA recently required food labels to list trans fat content.  Trans fat has still another detrimental health effect.  Trans fats interfere with and inhibit delta-4-, delta-5-, delta-6-desaturase conversion of short-chain essential fatty acids to beneficial longer-chain fatty acids(72-75).  So, in addition to avoiding NSAIDs, think twice about eating that gluten-free donut along with your deep fried chicken and french fries.

Getting Essential Fatty Acids into Your Diet

Understanding the fatty acid pathways is critical.  Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to be the most important and useful forms of omega-3 fatty acids to maintain health.  Conversion of alpha-linolenic acid to EPA in adult men is only about 8% and to DHA it is less than 0.1%.  In women, conversion to DHA is greater than 9%76.  Therefore, supplementation with or consumption of foods containing EPA and DHA has greater health benefit than intake of alpha-linolenic acid alone.  The richest and primary dietary source of EPA and DHA is consumption of oily fish.  Relying on this ecologically sensitive and limited food source to supply the entire world population with omega-3 essential fatty acids is problematic.  A thorough understanding of the fatty acid pathways could lead to large-scale EPA and DHA production from oilseed crops.  Alternately, corporations such as DuPont and BASF are engaged in research and development of genetically modified crops to produce EPA and DHA.  But there is consumer resistance to and concern about genetically modified crops.  Another potential new source of EPA and DHA is marine algae.  Commercial supplements containing DHA derived from marine algae are already being marketed to vegetarians.  Research to find suitable algae sources of EPA is ongoing with one Swiss company already claiming to have found such an algae.

Certain medical conditions and autoimmune disorders such as diabetes and atopic eczema as well as old age can cause deficencies of delta-6-desaturase, impeding not only conversion of alpha-linolenic acid to EPA, but conversion of linolenic acid to gamma-linolenic acid (GLA).   And if GLA is in short supply, so are DGLA and series 1 prostaglandins to reduce inflammation.  Therefore, if delta-6-desaturase levels are inadequate, GLA supplementation, in addition to EPA and DHA supplementation, may be useful.  Borage seed oil is the best source of GLA(77-78).

Food sources rich in the omega-6 fatty acid, linoleic acid (LA), include safflower, sunflower, soybean, corn, and sesame oils and seeds, as well as pecans, brazil and pine nuts.  Borage seed oil, evening primrose oil and black currant seed oil are rich in gamma-linolenic acid (GLA).  Oils rich in the omega-3 fatty acid, alpha-linolenic acid (ALA), are flaxseed, walnut, canola, soybean, and mustard as well as flaxseeds and walnuts themselves.  Since soybeans are much higher in LA than ALA, soybeans alone are not a good way to increase the ratio of omega-3 to omega-6 fatty acids.  In fact, with soybean products finding their way into almost every type of processed food, including so-called "health" foods, too much soy is a part of the problem of essential fatty acid imbalance in the modern Western diet.  Servings of herring, salmon, sardines, oysters, crab, trout, tuna and other fish provide EPA and DHA.  Soft-gel capsule fish oil supplements are readily available to provide EPA and DHA, but uncoated capsules can cause gastric upset and fishy aftertaste and odor in some individuals.  Enteric coated fish oil capsules, which delay the release of fish oil until it reaches the intestine, avoids this problem and may also improve absorption of EPA and DHA by up to 3 times45.  Independent testing has found essentially all major and reputable brands of fish oil supplements use purified fish oils containing extremely low and safe levels of mercury and other contaminants.  Check the label or the manufacturer's website for a statement of purity.  More detailed information concerning essential fatty acids, food sources, recommended daily doses, health warnings and contraindications can be found at the website:

• The Linus Pauling Institute Micronutrient Information Center
  Essential Fatty Acids
  https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

Maintaining adequate levels of essential fatty acids is crucial to good health.  Fat malabsorption due to celiac disease may result in deficiencies of omega-3 and omega-6 fatty acids, contributing to the wide range of symptoms associated with celiac disease.  There exist almost no studies of essential fatty acid levels in celiac disease patients.  An inadequate diet low in essential fatty acids could possibly even be a factor in the onset of celiac disease.  Supplementation with essential fatty acids, especially EPA and DHA omega-3 fatty acids, should strongly be considered when commencing a gluten-free diet after being diagnosed with celiac disease.

The Chemistry of Fatty Acids

Fatty acids are composed hydrogen and oxygen atoms bound to a long chain of carbon atoms.  The carbon atoms in the chain may be bound to each other by a single or a double bond.  This forms the basis for a chemical nomenclature used to identify the various fatty acids.  For example, the omega-3 fatty acid, alpha-linolenic acid, is designated as 18:3n-3.  There are 18 carbon atoms in the alpha-linolenic acid chain.  The total number of double bonds between carbon atoms in the chain is 3 (the first 3 in the formula.)  Finally, n-3 designates the position of the first double bond in the carbon chain, occurring 3 carbon atoms from the "omega" end of the chain.  The n-3 is also what classifies alpha-linolenic acid as an omega-3 fatty acid.  Linoleic acid is designated as 18:2n-6, and, hence, is an omega-6 fatty acid.  Omega-3 and omega-6 fatty acids are also commonly referred to as n-3 and n-6 fatty acids in scientific papers.

Alpha-Linolenic Acid (LNA) 18:3n-3  

  H H H H H H H H H H H H H H H H H OH
  | | | | | | | | | | | | | | | | | |
H-C-C-C=C-C-C=C-C-C=C-C-C-C-C-C-C-C-C=O
  | |     |     |     | | | | | | |  
  H H     H     H     H H H H H H H 
                                   ^

Omega End Position 1

The carbon atoms along the chain each have 4 bonds available.  Where a carbon atom has a single bond between its 2 neighboring carbon atoms in the chain, 2 bonds per carbon atom remain free to join with 2 hydrogen atoms.  Wherever a double bond between 2 carbon atoms occurs, each of the 2 carbon atoms loses one free bond, and there are 2 less bonds available for hydrogen atoms.  When hydrogen atoms are lost in a fatty acid conversion from a single carbon atom bond to a double bond, the fatty acid is said to be desaturated.  When there are no double bonds at all between carbon atoms in a fatty acid chain and all spaces are filled with hydrogen atoms, the fatty acid is said to be saturated.  Food manufacturers create hydrogenated fats by completely filling the chains with hydrogen atoms and partially hydrogenated fats by only partially filling the chains with hydrogen.  Essential fatty acid chains contain multiple carbon atom double bonds and are, thus, classified as polyunsaturated fatty acids.

You need to be familiar with this chemical nomenclature if you ever want to look up fat content in foods by searching the USDA National Nutrient Database.  The USDA database does not use the names of fatty acids, only their numerical designation.  https://fdc.nal.usda.gov/

Essential fatty acids exist in omega-3 and omega-6 families of short to long chain fatty acids which vary in number of carbon and hydrogen atoms.  Humans must at least include alpha-linolenic acid and linoleic acid in their diet.  In a process involving the enzymes delta-4-, delta-5-, delta-6-desaturase to remove hydrogen atoms, elongase enzymes to lengthen the carbon chain, and beta-oxidation to shorten the carbon chain, the human body can synthesize all the other important longer chain fatty acids needed from the short chain alpha-linolenic and linoleic acids.  The pathways for this synthesis are shown below.  The biochemistry of fatty acid synthesis is still not completely understood.  It was first proposed that an enzyme, delta-4-desaturase, existed and was needed for the synthesis of docosahexaenoic acid (DHA).  However, when delta-4-desaturase could not be found in or isolated from rat tissues, researchers proposed an alternate beta-oxidation pathway to replace the delta-4-desaturase pathway(60).  More recent research has been able to isolate delta-4-desaturase from single-cell organisms thereby supporting the original delta-4-desaturase concept(61).  Delta-4-, delta-5-, delta-6-desaturases remove hydrogen atoms by inserting double bonds between carbon atoms at positions 4, 5, and 6 counting carbons atoms in the carbon chain from the end opposite the "omega" end.

The Omega-3 Pathway

• Alpha-Linolenic Acid (LNA) 18:3n-3  → [delta-6-desaturase] →
• Stearidonic (Octadecatetraenoic) Acid (SDA) 18:4n-3 → [elongase] →
• Eicosatetraenoic Acid 20:4n-3 → [delta-5-desaturase] →
• Eicosapentaenoic Acid (EPA) 20:5n-3 ↔ [elongase] ↔
• Docosapentaenoic Acid  22:5n-3 ↔ [elongase] ↔ 24:5n-3 → [delta-6-desaturase] → 24:6n-3 → [beta-oxidation] → ( Alternate Pathway - Docosapentaenoic Acid  22:5n-3 ↔ [delta-4-desaturase] ↔ )
• Docosahexaenoic Acid (DHA) 22:6n-3 → [beta-oxidation] → 
• Eicosapentaenoic Acid (EPA) 20:5n-3 

The Omega-6 Pathway

• Linoleic Acid (LA) 18:2n-6 → [delta-6-desaturase] →
• Gamma-Linolenic Acid (GLA) 18:3n-6 → [elongase] →
• Dihomogamma-Linolenic Acid (DGLA) 20:3n-6 → [delta-5-desaturase] →
• Arachidonic Acid (AA) 20:4n-6 → [elongase] →
• Adrenic Acid 22:4n-6 ↔ [elongase] ↔ 24:5n-6 → [delta-6-desaturase] →    24:6n-6 → [beta-oxidation] →   ( Alternate Pathway - Adrenic Acid 22:4n-6 → [delta-4-desaturase] → )
• Docosapentaenoic Acid  22:5n-6

As mentioned earlier, the pro- and anti-inflammatory properties of prostaglandins produced from essential fatty acids are key to the benefits of consuming an adequate diet of omega-3 and omega-6 fatty acids in the proper ratio.  Prostaglandins are members of the eicosanoid family.  Eicosanoids are molecules generated from 20-carbon-atom fatty acids (DGLA, AA, EPA) and include prostaglandins, prostacyclins thromboxanes, leukotrienes, and lipoxins.   Prostacyclin prevents platelet formation and clumping involved in blood clotting and is an effective vasodilator.  Thromboxane encourages platelet and clot formation and is a vasoconstrictor, in contrast to prostacyclin.  Leukotrienes are inflammatory compounds involved in allergic and chronic inflammatory diseases, inducing bronchoconstriction in asthma.  Leukotriene B4 (LTB4) chemically attracts white blood cells to sites of bacterial infection or to foreign bodies including plaque in arteries, where the white blood cell activity increases the propensity of the plaques to rupture.  The series 4 leukotrienes derived from arachidonic acid (AA) are on the order of 5 times more potentially damaging than the series 5 leukotrienes derived from eicosapentaenoic acid (EPA).  Lipoxins are anti-inflammatory mediators inhibiting release of various inflammatory cytokines and leukotriene B4.  In addition to these compounds, recently identified anti-inflammatory and protective mediators called resolvins, docosatrienes, and neuroprotectins are derived from EPA and DHA.  The production of eicosanoids is summarized below(62-65).

Eicosanoidal Pathways

Series 1 (Anti-inflammatory):

• Dihomogamma-Linolenic Acid (DGLA) 20:3n-6
      → [cyclooxygenase (COX-1, COX-2)] →  PGH1 → [various synthases] →        PGE1, Thromboxane (TXA1)

Series 2 (Pro-inflammatory):

• Arachidonic Acid (AA) 20:4n-6
      → [cyclooxygenase (COX-1, COX-2)] → PGG2 → [peroxidase] → PGH2 → 
          [various synthases] →  PGD2, PGE2, PGF2, Prostacyclin (PGI2), 
          Thromboxane (TXA2)
      → [Lipooxygenase (LOX)] → HPETE (Hydroperoxyeicosatetaenoic Acid) → 
          [LOX] → Series 4 Leukotrienes (LTA4, LTB4, LTC4, LTD4, LTE4, LTF4), 
          Lipoxins (LXA4, LXB4)

Series 3 (Anti-inflammatory):

• Eicosapentaenoic Acid (EPA) 20:5n-3 
      → [cyclooxygenase (COX-1, COX-2)] → PGG3 → [peroxidase] → PGH3 → 
          [various synthases] → PGD3, PGE3, PGF3, Prostacyclin (PGI3), 
          Thromboxane (TXA3)
      → [Lipooxygenase (LOX)] → HPEPE (Hydroperoxyeicosapentaenoic Acid) → 
          [LOX] → Series 5 Leukotrienes (LTA5, LTB5, LTC5, LTD5)

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