American Heart Association OKs Linoleic Acid and Arachidonic Acid

Can the AHA be correct in promoting omega-6 PUFAs? Doesn't this conflict with the broad therapeutic action of omega-3 PUFAs, EPA/DHA, against inflammatory diseases?

The dietary shift from saturated animal fats to polyunsaturated fatty acids (PUFAs) from vegetable oils paralleled the shift from infectious diseases to inflammatory/degenerative diseases as predominant killers in the Western world. Treatments for degenerative diseases associated with aging have improved, but these diseases have become more prevalent and the age of onset has decreased. And medical costs have skyrocketed. Omega-6 vegetable oils seem to be the problem, but the American Heart Association (AHA) has recently given these PUFAs a clean bill of health.

Why the AHA Conclusions Seem Just Wrong

The rise of inflammatory/degenerative diseases follows the shift to processed foods rich in omega-6 PUFAs (corn, soy, cottonseed, safflower oils) and simple carbohydrates (grain starch, sugar, high fructose corn syrup), but the AHA presents scientific data to exonerate omega-6 PUFAs. The central problem is that the AHA’s conclusions are not based on a conceptual framework to explain cardiovascular disease. Instead, conclusions are derived from experiments in which various diets are fed to people and consequences are analyzed. With some diseases, in which there is a simpler cause and effect relationship, this approach might lead to useful answers, unfortunately, the inflammatory component central to cardiovascular disease can have multiple, alternative origins and simple experiments yield misleading conclusions.

Experimental Basis for AHA Support for Omega-6 PUFAs

• Conversion of short PUFAs found in the diet, e.g. LA, to the long PUFAs that serve as the precursors of cellular hormones. But conversion is thought to be inefficient, so that less than 1% conversion occurs and short PUFAs have little impact on cellular long PUFA concentrations. Moreover, the brain does not perform the conversion and the high brain content of DHA is supplied on demand from DHA circulating in the blood.
• There don’t appear to be any direct, inflammatory derivatives of LA (C-18), but after it is converted to AA (C-20), the arachidonic acid is the starting point for the conversion to most of the inflammatory and anti-inflammatory cellular hormones, e.g. prostaglandins, leukotrienes and lipoxins. Thus inflammation is initiated by AA-derived products, but resolution and return to normal physiology is also based on other AA-derived products.
• Increases in blood plasma AA are associated with anti-inflammation, not inflammation.
• Increases in dietary AA and/or LA result in a decrease in cardiovascular disease. Replacing dietary saturated fat with PUFA leads to a reduction of disease by 25-50%. Higher serum LA translates into less disease.
• Increases in dietary LA result in lower serum cholesterol and LDL, but paradoxically they also lead to a narrowing of arteries.
• The relative amounts of dietary PUFAs (USA) are LA 15grams/day, AA 0.15g/d, ALA (omega-3, C-18, linolenic acid) 1g/d, EPA/DHA <>

Statins Lower Cardiovascular Disease by Lowering Inflammation (LDL Not Important)

The JUPITER study showed that the statin Crestor was effective in lowering heart disease, because it lowered inflammation. Individuals with chronic inflammation responded to Crestor by lowering inflammation. Lowering of LDL levels, however, was not related to decreasing disease. Elevated LDL levels may reflect inflammation.

Relating the JUPITER results to the AHA conclusions suggests that LA and AA may reduce inflammation and as a consequence also reduce serum LDL.

Inflammation Is the Cellular and Tissue Response to Many Stresses

The list of pathogens that trigger inflammation is long and includes specific signals from viruses, bacteria, fungi and protozoa. Pathogen-caused damage, as well as physical trauma, cause inflammation. Disruption of cellular metabolism and energy flow by vitamin, mineral, amino acid, or fatty acid deficiencies or excesses all produce inflammation. One of the difficulties of diagnosis is the overlapping of symptoms originating from numerous sources of underlying inflammation. Herniation of vertebral disks, for example, can be triggered by physical trauma, but it also may be initiated by the intestinal inflammation of gluten-based celiac. Acne and depression are common symptoms of chronic inflammation that may result from dietary deficiencies, gum disease, gluten sensitivity, etc. All of these examples respond to anti-inflammatory diets.

It is difficult to identify the sources of inflammation in experimental studies. In cardiovascular disease, the sources of inflammation are commonly not known in individual cases and the cardiac symptoms are treated. In reality, these are actually many different diseases, all with different sources of inflammation, pigeon-holed under the same symptom, a cardiac event. The most effective long term treatment for the dispart group is general suppression of inflammation. Any specific treatment of a root cause only works on a small subset of the group and would be considered ineffective. Thus, statins are considered effective against heart disease, because they reduce inflammation that is common to the whole group. Reduction of LDL is inadvertently used as a measure of control of inflammation and has become inappropriately designated as a risk factor. Directly lowering LDL has no impact on heart disease, but it is easy to measure. Inflammation is hard to measure and finding the source of inflammation is harder still.

Omega-6 Vs. Omega-3 Is Another False Dichotomy

Just as there is no opposite to inflammation, omega-6 and omega-3 fatty acids are not in opposition. The action of aspirin is the big clue. Aspirin changes the structures of the enzymes involved in converting AA into inflammatory prostaglandins and leukotrienes, with the result that anti-inflammatory lipoxins are produced instead. Aspirin is a biochemical switch that mimics the natural transition of the cellular machinery from producing enzymes that accentuate inflammation, to enzymes and signals that are the next step in the cycle, repair and restoration of normalcy.

Omega-6 PUFAs are needed for both inflammation and restoration of normal cellular functions. Some of the enzymes produced during inflammation are needed for the reset to normalcy. The difficulty comes when inflammation is sustained, components are depleted and the cycle cannot be completed. The result then is chronic inflammation, the symptoms of metabolic syndrome and degenerative diseases.

Why Did Demonizing LA and AA Seem Right?

It seems wise not to trust medicine, dietitians and the food industry, because they have made so many lamentable mistakes making dietary suggestions that have shortened so many lives. Professional societies like the AHA also frequently give silly advice, because the advice doesn’t reflect the best information from the biomedical literature. So it makes sense to be skeptical.

In this case the AHA appears to be right, only because established views were supported by straightforward experiments. What determines if an excess of dietary LA and AA is going to be a problem with inflammation is the absolute amount of AA and EPA available on the surface of immune cells. PUFAs are attached as part of the phospholipids of the lipid rafts on the membrane surface of immune cells that have received a inflammatory signal, e.g. bacterial lipopolysaccharide. There is usually adequate AA to be converted by enzymes on the cell surface to produce further inflammatory signals. The problem comes if there is so much AA that the EPA never made it to the lipid rafts. The result would be inadequate EPA conversion to anti-inflammatory prostaglandins and failure to return to normalcy. This would be a particular weakness in the presence of a large depletion of the EPA pools during sustained inflammation and chronic inflammation would result.

Thus, the AHA promotion of omega-6 PUFAs is half right. They should have said that omega-6 fatty acids are not a problem, if there is adequate EPA/DHA and no sustained inflammation. Unfortunately, the Western diet provides inadequate EPA/DHA and deficiencies that constantly produce inflammation. Of course, those enjoying an anti-inflammatory diet and lifestyle have biochemical tolerance for the AHA’s suggestions. Others eat vegetable oils at their peril.

reference:

Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F. 2009. Omega-6 Fatty Acids and Risk for Cardiovascular Disease. A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009 Jan 26. [Epub ahead of print]

Where’s the Aspirin?

Aspirin is the traditional anti-inflammatory agent. Many of us grew up with the quintessential doctoring phrase, “Take two aspirin and call me in the morning.” Aspirin stops inflammation in several ways. Like all drugs, it interacts with many different proteins/enzymes. In fact it interacts so intimately with the inflammatory system that it suggests that the process of inflammation may require an aspirin-like molecule to function normally.

Aspirin Binds to Multiple Enzymes of Inflammation

Aspirin is observed to reduce inflammation. That means that ingested aspirin tablet dissolve in the stomach and pass through the intestines into the blood stream and subsequently bath cells of the blood and the endothelium that lines the blood vessels. In order to reach the blood stream, the aspirin must pass through the intestinal cells. That passage requires binding to a protein transport molecule.

Cells responding to an inflammatory signal (NFkB, transcription factor is activated) synthesize enzymes that release unsaturated fatty acids (ARA, EPA, DHA) from membrane phospholipids (PLA2, phospholipase A2), form a cyclic epoxide from the fatty acid (prostaglandin H2 synthase 2, also called cyclooxygenase 2, COX-2).

Aspirin binds to the inhibitor that normally inactivates NFkB and prevents NFkB activation that is required for inflammation. Aspirin also binds to PLA2 and prevents fatty acid release and thereby blocks activation of inflammation. Aspirin also binds to COX-2 and blocks the production of inflammatory prostaglandins from ARA. But that is not all that aspirin does.

Inflammation Resolution Uses Aspirin-COX-2 Interaction

The strange interaction that makes aspirin suspicious is that aspirin doesn’t just interfere with the action of enzymes, it subtly changes their specificity. Thus aspirin chemically transfers its acetyl group (CH3-COOH-) to an amino acid in the active site of COX-2 to produce a new group of anti-inflammatory lipoxins from ARA, EPA and DHA.

This raises the question of whether aspirin is a natural dietary modulator of inflammation. Recall that aspirin was initially obtained from willow (Salix) bark. Unfortunately, the data are conflicting. Initial research indicated that grains (naturally inflammatory) lacked aspirin, but many herbs, spices and leafy vegetables (naturally anti-inflammatory) contained aspirin. Subsequent tests refuted this work. It would be consistent with observations that some dietary components are anti-inflammatory, but candidate acetyl donors have not been identified.

Speculative acetyl candidates may include the menthol relatives, such as menthyl acetate (figure). Peppermint oil, which contains mostly menthol with some menthyl acetate, is more effective in the treatment of inflammatory bowel disease than most pharmaceuticals prescribed to treat the condition. This anti-inflammatory activity may be due in part to the aspirin-like chemical structure and function of the menthyl acetate. Also note that acetic acid/vinegar is sometimes suggested as a cure-all. This activity may be a consequence of its formation of ester linkages with alcohols that have structures similar to menthol.

Large Dose Aspirin as Cancer Treatment

The potent anti-inflammatory effects of aspirin have been compromised, because inflammation is an essential developmental activity. Thus, the integrity of the gut, for example, requires modest production of inflammatory prostaglandins and a pill of aspirin can disrupt gut tissue. Large doses of aspirin cannot be given orally. Intravenous administration of large doses of aspirin, however, is possible and the impact on process that require inflammation is dramatic.

Anecdotal evidence indicates that large dose aspirin is able to disrupt cancers, because proliferation of cancer cells requires NFkB activation and other inflammatory responses. High doses of aspirin also cause other potentially dangerous complications, such as short-circuiting oxidative phosphorylation of mitochondria and increasing nitric oxide free radical production. Still, the impact of high dose aspirin on some diseases is so amazing that it is being actively and carefully pursued.

Brain Arachidonic Acid: Alzheimer’s, Bipolar, Parkinson’s

A recent review article on brain lipid metabolism discussed the results obtained by looking at how the major omega-6 fatty acid, arachidonic acid is imported and used in brain tissue. Arachidonic acid conversion to inflammatory prostaglandins was monitored by extracting lipids from rat brains after a variety of treatments. Similarly, isotopes (13C) of fatty acids were imaged by PET scans in patients treated for Alzheimer’s, bipolar disorder and Parkinson’s disease.

The major findings on brain arachidonic acid (AA, omega-6) and docosahexaenoic acid (DHA, omega-3) are:

• Ca. 5% of daily dietary AA and DHA are converted to make prostaglandins in the brain. Converted AA and DHA are rapidly replaced by serum AA and DHA.
• Brain DHA and AA metabolisms are independent.
• AA and DHA are rapidly circulated into phospholipids (R2 on the diagram) on the endoplasmic reticulum, move to the cytoplasmic membrane (see diagram, gray and white strands) removed by phospholipase A2 in synapses, converted to prostaglandins, leukotrienes, etc., or recycled to phospholipids. Enzymes that catalyze these reactions are usually different for DHA and for AA.
• 
• Drugs used to treat bipolar disorder (lithium, carbamazepine, valproic acid, lamotrigine) lower AA conversion in rats, but do not affect DHA conversion.
• Experimentally induced brain inflammation or neurotoxicity increases AA conversion, but not DHA conversion to prostaglandins.
• An omega-3 fatty acid deficient diet also increases AA, but not DHA conversion.
• More AA is converted in Alzheimer’s patients. This is consistent with increased inflammation and neurotoxicity in postmortem examinations.
• Mice that have been genetically manipulated to eliminate alpha-synuclein, a protein implicated in Parkinson’s disease, also show an increase in AA conversion and a decrease in DHA conversion.

Interpretation: Inflammation in the brain is separate from the rest of the body, but is the foundation of many brain disorders, including Alzheimer’s disease, bipolar disorder and Parkinson’s disease. In these disorders, arachidonic acid is rapidly converted into inflammatory prostaglandins and leukotrienes. Drugs that reduce symptoms, reduce AA conversion.

A diet rich in omega-3 DHA and reduced omega-6 arachidonic acid reduces the symptoms of these diseases -- an anti-inflammatory diet and lifestyle should be the first line of defense against brain/mental disorders.

reference:
Rapoport SI. 2008. Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fatty Acids. Oct 28. [Epub ahead of print]

Bee Sting Allergy

Typical. I started to write an article on leukotrienes, the inflammatory derivatives of the omega-6 fatty acid, arachidonic acid, but ran across another powerful example to test my hypothesis to explain the cause of allergies. The leukotriene article will have to wait till another day.

Wikipedia is my source of choice for up-to-date summaries of biomedical information. I queried “leukotrienes” and immediately ran across the original name for these inflammatory compounds, “slow reacting substance of anaphylaxis”. I was initially distracted by the classic experimental use of snake venom and histamine to induce leukotriene production. Snake venom has the same enzyme, PLA2, as brown recluse spider venom (subject of a previous article) and honey bee venom, that releases arachidonic acid (ADA). ADA is an omega-6 fatty acid that is the starting material for inflammatory prostaglandins and leukotrienes.

The mention of honey bee venom in the Wikipedia article on anaphylaxis sent me on a quick check of the structure and sequence of the honey bee allergen. I initially found that the major allergen is a hyaluronidase. I quickly searched for a three amino acid sequence that I predicted would make it an allergen. It was just where I expected to find it. About two thirds of the way along the amino acid sequence I found, -TTSRKKVLP-. Three basic amino acids together, in this case -RKK-, argininine-lysine-lysine, form a strong heparin-binding domain, that I believe takes proteins into cells and during inflammation primes the immune system for allergic responses.

I have found the same strong heparin-binding domain associated with allergens of ragweed, dust mites and peanuts. The principal autoantigens of autoimmune diseases, such as lupus, celiac, etc. also display the same unusual sequences. In lupus, or example, nuclear proteins with the internalization signal provided by nucleic acid-binding domains (and nuclear localization signas) are autoantigens. This pattern is found with all allergens that I have examined. There are a few apparent exceptions, but in all of these cases, there is a closely related allergen from a related source that has the expected strong heparin-binding domain. It appears that in these cases, the less common allergen provides the initial exposure during the presentation phase of high inflammation, and the allergy is maintained by subsequent exposure to the more common allergen. After the establishment of the allergy, the strong heparin-binding domain is no longer needed, because antibodies bind to other parts of homologous allergenic proteins for internalization.

Just for fun, I have illustrated the honey bee allergen, hyaluronidase, to show both its strong heparin-binding domain (blue) along with its substrate hyaluronan (grey and red). Note that the substrate sugars are in the slot of the active site, which is lined with orange and yellow aromatic amino acids that provide flat, hydrophobic binding platforms for each sugar.

After this little distraction to provide further support for my explanation of the cause of allergies, I have to get back to looking at the role of leukotrienes in anaphylaxis, COPD, asthma and other inflammatory diseases.

Spider Inflammation

Happy Halloween! It's time for creepy, crawly things that bite... and cause inflammation.

The brown recluse has the bite that keeps on giving. Its venom contains a phospholipase that cleaves membrane phospholipids to release arachidonic acid (omega-6 fatty acid precursor of inflammatory eicosanoids) and lysophosphotidylcholine that binds to multiple receptors to signal NFkB-based inflammation.

It’s Halloween and a time to talk about things that bite and sting. After all, the symbol of Halloween is the Jack-O-Lantern, the flame within, i.e. inflammation. Venom is Nature’s answer to the need for instant inflammation.

The brown recluse is adapted for hunting, killing and eating. The killing bite is the subject tonight. The recluse injects a venom designed to get the biggest bark for the bite. It uses the least amount of protein to immobilize its prey/meal. Of course, since spiders are suckers, it helps if the venom also liquifies its meal.

The venom also has a secondary use as a defense. In this case, if something too big to eat encounters a brown recluse, the goal is to encourage the big beast, you or me, to leave. No pain, no gain.

Venom provides a convergence of enhanced meal making and avoidance of being made into a meal. The answer is, of course, enzymatic inflammation. Venom contains enzymes that convert common cellular components into potent pyrogens, inflammation inducers. The wicked witch of the world of inflammation is phospholipase A2 (PLA2).

Brown recluse venom PLA2 clips off the arachidonic acid from membrane phospholipids and leaves an amphipathic detergent, lysophospholipid (LPL). The LPL can destabilize membranes and rupture cells. It is also a potent activator of several cell receptors that signal inflammation via NFkB. The COX-2 induced by inflammation has a readymade substrate present, arachadonic acid, and produces inflammatory prostaglandins, that continue the signaling frenzy. The result is inflammation, pain and necrosis.

Recluse bites are hard to treat. I think that some people recommend topical application of gunpowder. I guess that would make sense, because one of the problems of recluse bites is actually constriction of blood flow by other venom components, and nitroglycerin patches apparently provide some relief. Both the patches and nitrates of the gunpowder cause vasodilation, and would remedy some of the circulation problems of the venom. Glucocorticoids are also partially effective, since they are anti-inflammatory. Then there is heparin. I would always try heparin, at least as a last resort, because heparan sulfate proteoglycans are an essential component of most extracellular signaling systems, e.g. cytokines. Heparin should disrupt or activate all of these systems. It is unpredictable. It turns out that heparin is helpful against the brown recluse. I would also like to try a topical potion made of Vick’s Vaporub (menthol, eucalyptol, camphor, turpentine), castor oil and heparin. That should fix about anything. It even smells good, sooths painful joints and makes your skin soft.

Happy Halloween. Enjoy trick or treating, but watch where you put your hands.