5

votes

Baffled by Eicosanoid Pathways and Dietary LA, O3, O6, AA etc.

Answered on September 12, 2014
Created February 28, 2011 at 3:40 PM

I am somewhat confused by the eicosanoid pathways (OK, extremely confused..) and the implications of dietary AA, O3, O6, LA etc. There is so much conflicting information out there, even some of the guys we hold in highest regard can't seem to agree.

Most recently, I've been set in Dr. KGH's camp of keeping all PUFA to an absolute minimum. However, I was reading my copy of Protein Power by Dr. Eades last night, and saw something I guess I'd missed before- "Your first task is to eat a diet that provides you with plenty of linoleic acid- the essential fat from which all the eicosanoid messengers are made." He does say to keep alpha linolenic acid to a bare minimum, with the ultimate goal of minimizing arachidonic acid production. Dr. Sears of the Zone has a similar idea, AA being a "toxic" fat. Then you've got Dr. William Davis of heartscanblog saying alpha linolenic acid is actually very beneficial.

I've seen the evidence of tissue concentration of Omega 6 and increased heart disease risk on Stephan Guyenet's blog and others'. So how is it that these other guys are advocating high LA, ALA whatever intakes? It can't just be that they're chalking it up to lowered cholesterol levels, can it?

So what is the difference between dietary and body-derived arachidonic acid? Should we not eat so many egg yolks and avoid conventionally raised beef (apparently pastured has little AA)? Eades talks about elevated insulin unfavorably effecting the eicosanoid pathways... we've got that covered with paleo. So how else do we optimize eicosanoid production?

I feel like I am missing something, maybe even a small detail that will suddenly give me an "aha" moment and solidify my conceptualization of all this.

So much name dropping, so many questions AAAHHH help me!!!

I want to eat almonds again haha.

4145b36f1488224964edac6258b75aff

(7821)

on March 06, 2011
at 03:43 PM

Citing sources is usually considered good form.

4e40d2b9e1a762949a25b958762aa10d

(762)

on March 05, 2011
at 07:58 PM

Who is the researcher? Cite your sources.

Be1dbd31e4a3fccd4394494aa5db256d

(17969)

on March 05, 2011
at 07:23 PM

Exactly what is the fate of all of that LA that doesn't get converted? I have read about hanging out in the cells and blocking thyroid hormone transduction but I don't know the whole story.

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 06:41 PM

Helen I used to as well but nuts have two problems for me.....lots of omega 6 and too many carbs. I know that nuts supply alot of fat content but they also have carbs and people forget that point. The only nut I will eat regularly is a macademia nut. If I am eating fish with known mercury issues I eat a few brazil nuts to offset that.

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 06:39 PM

supports all the above comments i have sourced to the person asking the question that went unanswered for 5 days.

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 03:25 AM

and explains the confusion completely. Once you understand the biochemistry of the receptors and how all nine interplay you can begin to understand how a class of chemicals acts both inflammatory and anti inflammatory based upon the context of the chemistry they find themselves in. This question went unanswered for a good amount of time and I knew where to look for the definitive answer.

5edbf85deaf83e13b176df023abb154d

(1293)

on March 05, 2011
at 02:36 AM

This "Dr. K" comment was cut-and-pasted from: http://themedicalbiochemistrypage.org/eicosanoids.html

1acc4ee9381d9a8d998b59915b3f997e

(2099)

on March 01, 2011
at 03:54 PM

I eat nuts a little...about 1/4 cup or so of pecans a two or three times a week. Btw, I make my mayo with olive oil and coconut oil.

Cf5c9ba3c06cf300ae23c52778dfd317

(545)

on March 01, 2011
at 04:06 AM

Yeah I eat a fair amount of sardines and salmon. Do you eat nuts at all?

2507b557331c8a674bc81197531e609a

(4994)

on February 28, 2011
at 04:50 PM

I like this question, you have articulated it brilliantly :D

  • Cf5c9ba3c06cf300ae23c52778dfd317

    asked by

    (545)
  • Views
    2.1K
  • Last Activity
    1496D AGO
Frontpage book

Get FREE instant access to our Paleo For Beginners Guide & 15 FREE Recipes!

4 Answers

1
Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 12:59 AM

The principal eicosanoids of biological significance to humans are a group of molecules derived from the C20 fatty acid, arachidonic acid. Additional biologically significant eicosanoids are derived from dihomo-??-linolenic acid (DGLA) which is produced in the reaction pathway leading to arachidonic acid from linoleic acid. The major source of arachidonic acid is through its release from cellular stores. Within the cell, it resides predominantly at the C???2 position of membrane phospholipids and is released from there upon the activation of PLA2. PLA2 is inhibited by steroid medications used in clinical medicine. The immediate dietary precursor of arachidonate is linoleic acid. Linoleic acid is converted to arachidonic acid as well.

The eicosanoids produce a wide range of biological effects on inflammatory responses.....on the intensity and duration of pain and fever, and on reproductive function (including the induction of labor). They also play important roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis.

The eicosanoids consist of the prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and lipoxins (LX). The PGs and TXs are collectively identified as prostanoids. PG's were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. The lipoxins are anti-inflammatory eicosanoids synthesized through lipoxygenase interactions (hence the derivation of the name). Lipoxins are potent anti-inflammatory eicosanoid derivatives and their synthesis can be increased in response to ingestion of aspirin. An additional class of anti-inflammatory lipid compounds, whose syntheses can also be triggered by aspirin, are the resolvins (Rv) and the protectins (PD) Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from membrane phospholipids. The major dietary sources of GLA (where eicosanoids come from) are borage oil, evening primrose seed oil, hemp seed oil, and black currant seed oil. Diets containing sources of GLA have been shown have distinct cardiovascular benefit similar to diets rich in omega-3 polyunsaturated fatty acids such as is found in cold water fishes.

Each of the eicosanoids function via interactions with cell-surface receptors that are members of the G-protein coupled receptor (GPCR) family. There are at least 9 characterized prostaglandin receptors. This very fact is why many are confused by eicosanoids. The ligand receptor complexes all have different functions and purposes. Receptors that bind the prostaglandin D family of lipids are called the PGD receptors and those that bind E family prostaglandins are called the PGE receptors. The PGD receptors are coupled to the production of cAMP and activation of PKA. The PGE receptors couple to the activation of PLC?? and as a consequence the production of DAG and IP3 from membrane phospholipids. The receptor for prostacyclin (PGI2) is called the PC receptor and it couples to production of cAMP. There are 2 receptors that bind LTB4 called BLT1 and BLT2. The peptidoleukotrienes (cysteinyl leukotrienes) bind to receptors called CysLT1 and CysLT2. The thromboxane receptor is coupled to the activation of PLC??.

The major actions of the series-2 prostaglandins and thromboxanes (predominantly PGE2 and TXA2) are pro-inflammatory as are the series-4 leukotrienes (predominantly LTB4). Thus, it makes sense that drugs that reduce the production of these compounds would be beneficial at reducing inflammation and the associated vascular pathologies. This is where aspirin and NSAIDs act on this system for its effects.

Research over the past 10???15 years has demonstrated the physiological benefits (i.e. anti-inflammatory) of alternative pathways of polyunsaturated fatty acid metabolism. Here is where it get confusing.....because they also have inflammatory and anti inflammatory effects. I will lay the reason out and you can re read it a few times.

The synthesis of arachidonate, much of the DGLA derived from ingested linoleic acid or GLA is diverted into membrane phospholipids due to the inefficiency of the ??5-desaturase catalyzing the conversion of DGLA to arachidonic acid. Incorporation of DGLA into membrane phospholipids competes with the incorporation of arachidonate so that diets enriched in GLA result in an alteration in the ratio of membrane arachidonate to DGLA. Release of membrane DGLA occurs through the action of PLA2 just as for release of arachidonate. Once DGLA is released it will compete with arachidonate for COXs and LOXs. The products of COX action on DGLA are series-1 prostaglandins (PGE1) and thromboxanes (TXA1). These eicosanoids are structurally similar to the series-2 eicosanoids except, of course, they have a single double bond. Although structurally similar, the series-1 eicosanoids have distinctly different biological actions. And this is why there is a ton of confusion of what this class of fats does.......PGE1 and TXA1 are anti-inflammatory, they induce vasodilation, and they inhibit platelet aggregation. When DGLA is a substrate for 15-LOX the product is 15-hydroxyeicosatrienoic acid (15-HETrE). 15-HETrE is a potent inhibitor of 5-LOX which is the enzyme responsible for the conversion of arachidonic acid to LTB4. LTB4 is a potent inflammatory molecule through its action on neutrophils, thus, DGLA serves to inhibit inflammation via the linear eicosanoid pathway as well. The more omega 6 oils you eat with lineolic acid the more this favors this breakdown to the inflammatory eicosainoid production and hence a rise in your cardiac CRP in inflammation measurement.

Due to the vasodilating action of PGE1 it is used pharmaceutically as aprostadil for the treatment of erectile dysfunction (ED). The ED applications of PGE1 are sold as MUSE?? and Caverject??. MUSE is a urethral suppository and Caverject is an injectable version. Aprostadil is also used clinically to treat newborn infants with ductal-dependent congenital heart disease.

Moreover, because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity [e.g. Celebrex?? (celecoxib), Prexige?? (lumiracoxib) and the recently removed Vioxx?? (rofecoxib) and Bextra?? (valdecoxib)]. Unlike the effects of aspirin on the action and synthesis activities of COX-2, this latter class of drug does not induce the synthesis of anti-inflammatory lipids. In fact the cardiac benefits of low-dose aspirin are negated when taken along with COX-2 specific inhibitors such as Celebrex, which remains a heavily prescribed NSAID today.

The resolvins (Rvs) have anti-inflammatory actions that lead to the resolution of the inflammatory cycle, hence the derivation of their names as resolvins (resolution phase interaction products). The resolvins are synthesized either from eicosapentaenoic acid (EPA, an essential omega-3 polyunsaturated fatty acid) or from docosahexaenoic (DHA, also an omega-3 fatty acid).

The D series resolvins are derived from DHA and the E series from EPA. An additional anti-inflammatory lipid derived from DHA is protectin D1 (PD1). Aspirin can trigger the synthesis of an epimeric protectin D1 compound as well as epimeric resolvin D series compounds. The switch from synthesis of pro-inflammatory eicosanoids, such as the prostaglandins and the thromboxanes, to the pro-resolving lipoxins, resolvins, and protectin D1, occurs via induction of 15-LOX. Disruption of COX-2 or inhibition of LOX enzymes results in a disruption in the normal process of inflammation resolution.

So the short answer to your confusion is due to the shear number of receptors that eicosanoids bind to lead to their pro and anti inflammatory effects. Dietary intake heavily favors the pro inflammatory pathways so that is why omega 6's are frowned upon in paleo.......but there is a good side to some omega six pathways as they are potent vasodialators and very anti inflammatory based upon the actions and receptors they bind. This give you the complete answer and I am sure will confuse you further but at least its all here in one place for you to read until you get the fact that eicosaindoids use an equalizer system of receptors to give a wide spectrum of effects to fine tune cellular function based upon dietary choices. We can't live without omega 6's but the ratio of them to omega three's is of vital importanceto our health and inflammatory status one way or the other. The optimal ratio is still not known but it is believed to be 3 to 4 to one 6's to 3's in order to keep the pro inflammatory portions of omega 6 oils under wraps. The SAD has 25 to 40 to 6's to three ratios thereby pushing us to receptors that favor the pro inflammatory sides of the eicosanoids and they become the chemicals that lead to AGE's and ALE's that cause disease, obesity, leptin resistance, and activation of NF kappa beta, IL6 and IL 2 and TNF alpha and the cancer pathways and we use the cardiac CRP to monitor that status as a PROXY.

5edbf85deaf83e13b176df023abb154d

(1293)

on March 05, 2011
at 02:36 AM

This "Dr. K" comment was cut-and-pasted from: http://themedicalbiochemistrypage.org/eicosanoids.html

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 03:25 AM

and explains the confusion completely. Once you understand the biochemistry of the receptors and how all nine interplay you can begin to understand how a class of chemicals acts both inflammatory and anti inflammatory based upon the context of the chemistry they find themselves in. This question went unanswered for a good amount of time and I knew where to look for the definitive answer.

4145b36f1488224964edac6258b75aff

(7821)

on March 06, 2011
at 03:43 PM

Citing sources is usually considered good form.

0
Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 06:32 PM

I went on a search this morning and found this to support my views on this.....its from the THINCS group site and I thought it may help the overall discussion for completeness.

You may be interested in the following response I received from an essential fatty acid researcher at a North American university. Comments?

Dietary linoleic acid (LA, n-6) plus arachidonic acid (AA, n-6) are the two sources of cellular AA in the human body. The typical N. Am. consumes about 15,000 mg/day of LA (and converts approx. 1-2 % or 150-300 mg/day into AA via biosynthesis as a precursor). We eat only 100-200 mg of preformed AA/day. One might expect that a vegan vegetarian (who never consumes any AA ) would have about half the cellular level of AA. However, the AA levels in such subjects are only moderately lower thereby supporting the rather more efficient conversion of LA to AA when AA is not consumed. AA, when available, can exhibit feedback control/inhibition of LA conversion to AA. LA conversion to AA in also reduced somewhat by higher omega-3 intakes although this is a relatively minor factor currently in N. Am. because of our high omega-6: omeg a-3 (approx. 10:1) ratio. Lowering the intake of LA and/or AA plus elevating the intake of omega-3 (LNA and particularly EPA/ DHA) can all be expected to reduce the formation of AA and AA-derived eicosanoids (incl. pro-inflammatory leukotrienes/cytokines).

Be1dbd31e4a3fccd4394494aa5db256d

(17969)

on March 05, 2011
at 07:23 PM

Exactly what is the fate of all of that LA that doesn't get converted? I have read about hanging out in the cells and blocking thyroid hormone transduction but I don't know the whole story.

4e40d2b9e1a762949a25b958762aa10d

(762)

on March 05, 2011
at 07:58 PM

Who is the researcher? Cite your sources.

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 06:39 PM

supports all the above comments i have sourced to the person asking the question that went unanswered for 5 days.

0
2507b557331c8a674bc81197531e609a

(4994)

on February 28, 2011
at 04:59 PM

It's probably a good idea to limit nuts, eat them, just not in huge quantities. I Eat saturated fat from pastuered animals, organ meats are good if possible, some oily fish, bit of olive oil on my salads, clarified grass fed butter, coconut oil and if, and only if I have been exposed to excess omega 6 I will supplement with fish oil. An analogy I heard (I think it was Chris Kresser) was that if you leave fish oil on the side it will go rancid much qicker than saturated fat, the same applies in your body, if you have not used the fish oil as energy and it is stored, it can go "bad" in your bady (easily oxidised) crudley put I know sorry.

0
1acc4ee9381d9a8d998b59915b3f997e

(2099)

on February 28, 2011
at 04:41 PM

It all baffles me, too, so I don't worry about it. I stay away from seed oils like soy, corn and canola, etc. I also stay away from mass market mayo. I eat tuna and sardines, use butter, coconut oil and homemade mayo and call it good enough.

1acc4ee9381d9a8d998b59915b3f997e

(2099)

on March 01, 2011
at 03:54 PM

I eat nuts a little...about 1/4 cup or so of pecans a two or three times a week. Btw, I make my mayo with olive oil and coconut oil.

Cf5c9ba3c06cf300ae23c52778dfd317

(545)

on March 01, 2011
at 04:06 AM

Yeah I eat a fair amount of sardines and salmon. Do you eat nuts at all?

Ed71ab1c75c6a9bd217a599db0a3e117

(25482)

on March 05, 2011
at 06:41 PM

Helen I used to as well but nuts have two problems for me.....lots of omega 6 and too many carbs. I know that nuts supply alot of fat content but they also have carbs and people forget that point. The only nut I will eat regularly is a macademia nut. If I am eating fish with known mercury issues I eat a few brazil nuts to offset that.

Answer Question


Get FREE instant access to our
Paleo For Beginners Guide & 15 FREE Recipes!