User:Pdeitiker/Arachidonate sensitivity

Sensitivity Arachidonic Acid

Arachidonate (commonly called Arachidonic acid) occurs in various forms in the body, but generally as esters of triacylglycerol or hormone esters. Arachidonate is a proinflammatory agent and is metabolically derived from linoleic acid or through the diet from animals. Arachidonic acid is converted by the body into Prostaglandin E2 (PGE2) and hydroxyeicosatetraeinoate (HETE). PGE2 is responsible for many inflammatory responses often involving painful cramping or soreness. HETE is implicated in metastatic cancer. Arachidonate metabolism in the body is controlled by genetic and environmental factors. One of the regulators of Arachidonate production and conversion to PGE2 is omega-3 fatty acids. The genes responsible for synthesis of arachidonate are variable in the human population. And combinations of higher levels of conversion coupled with elevated dietary sources maybe a factor in sensitivity to arachidonic acid.

LDL and HDL account for at least some of the inhibition of AA metabolism produced by plasma.

Rheumatoid Arthritis
In rheumatoid arthritis the synovial membrane become irritated and thickened. Early studies of rheumatoid arthritis reveal that extracts of synovial membrane produced PGE2 and a small amount of PGF2 when incubated with arachidonate. This response can be inhibited with anti-inflammatory drugs, such as aspirin. The cells that cause this inflammation have characteristics of macrophages, which appear to respond to and also synthesize PGE2 from arachidonic acid. Early studies found that arachidonic acid was frequently lower on blood of arthritis patients.

Indocrine pathology
The lipid product, HETE of ω6A oxidation have been implicated in diabetic nephropathy. This caused an increase of the Type 1 angiotension II receptor and amplified the signaling effect of Angiotension II. In diabetic mice, the increase in Angiotension II leads to an increased rate of oxidatidation of ω6A, in a positive feedback mechanism.

Breast pathology
In breast cancer, tesmilifene, a drug that augments the effect of doxorubicin, was postulated to modulate the intracellular concentration of the arachidonate product HETE, which is implicated cancer cell proliferation and metastasis.

Prostate issues
Diets high in omega-6 fatty acids are associated with an increased risk of bone metastasis from prostate carces (PCa). Arachidonate is a potent mitogenic, stimulating the production growth controlling enzymes. These enzymes stimulated growth of bone marrow stromal cells, a possible precursor to bone cancer. COX-2 inhibitors blocked the effects of Arachidonate.

Animal Feeding Controversy
A major concern for the adverse health effects of ω6A comes from the high relative levels of ω6A in modern fat sources, along with higher levels of dietary fat intake from animals. Omega-3 (alpha) linolenate (ω3L) is the precursor of biologically important ω3 fats found in animals. Omega3L is generally low or absent in plant seeds like yellow corn (miaze), sunflower seeds, olives, plants which contain ω6L, however ω3L is high in flax seeds. Omega3L is a preferential oil in the leaves, stems and often seeds of cold climate plants as it acts as 'antifreeze' for cell membranes of these plants, it is also found in pasture grasses in varying amounts. Other fats however influence the hardening of seeds, that dry and germinate in the next appropriate season. Grazing bovids, such as cattle, tend to naturally take a large percentage of the diet as whole grasses. The complicated digestive system of ruminants has evolved for the digestion of cellulose and complex carbohydrates in grasses ('slow carbs'), and sources of fast carbs, sugar and simple starches, may damage the gut of these animals.

Feedlot deprivation
In feedlot 'finished' cattle, animals are deprived of vegetation (grass leaves, stems) and fed a large proportion of the diet in seeds low in ω3L, high in starch and ω6L. In the western US, the primary feed grain is dried yellow corn. These seeds have been selected for high starch content but have no ω3L. A common practice is to finish animals for a 4 month period which generally results in a higher risk of infection requiring antibiotic supplimentation. The commonly eaten parts of these animals become depleted ω3-fats, whereas the amount of ω6A stored in muscle fat increases. The Union of Concerned Scientists advocates a reduction of feedlotting of cattle. A recent review of literature concluded that range-fed cattle were healthier at the time of slaughter, needed fewer antibiotics and had higher levels of omega-3 fats than lot fed cattle. Of course this study also reflects the agenda of UCS toward environmental concerns of feedlots. The increase in 'finishing' times brought about by the use of antibiotics to keep animals alive may explain the rise of certain diseases in which ω6A plays a role. Their are addition issues with this process. The higher levels of starch and lower cellulose in the feed may contribute to higher amounts of cholesterol and saturated fats. When consumed by people is a factor in the increase of serum cholesterol and low-density lipoproteins in humans. High cholesterol levels inhibit the degradation of ω6L and ω6A.

Replacement meats
In markets where the majority of beef is feedlot-finished, there are comparable replacements such as buffalo-meat (American bison meat) and Grass-finished beef (called grass-fed). However, these products such as 'grass-fed' beef and buffalo can demand a premium price. Other animals such as turkey and chicken have higher levels of ω3-fats relative to ω6A and can be used as protein source. Wild boar, a pest species in many areas, may have no-limit on hunting and is also a good source of lean red-meat. Less comparable replacements are fish and shellfish. The highest content of ω3-fats to ω6A can be found in cold or deep-water fishes (salmon, atlantic cod), shellfish (winter oysters, New Zealand Clam), and krill. While plant sources like flax seed have abundant ω3L, the oil is not as readily absorbed as oil from fish, much of which is converted into biologically useful form. The increase in ω3-fats is not so affective at blocking arachidonic acid as it is in regulating ω6L conversion to ω6A. Therefore it may be affective at preventing sensitivity at lower levels of dietary ω6A, there may be a limit of effect in adding ω3-fats to the diet, in very sensitive individuals requiring the elimination of graxing land mammals from the diet.

Causes
Arachidonate is an essential fatty acid (EFA), however, unlike other EFAs, it does not always need to be derived from the diet, since arachidonate is synthesized from linoleic acid. In strict herbivores all arachidonate is made in the body, whereas in strict carnivores, all arachidonate comes from the diet. In omnivores the level of arachidonic acid that is made depends on arachidonate in food, the availability of linoleic acid, and the genetic regulation of synthesis. The genetics of arachidonate sensitivity has not been well defined in people. However, people settled around the world the evolved toward and adapted to new diets. In certain regions of the world, such as pre-Neolithic Western Europe, maritime food sources such as oysters were a constant and majority component of the diet, exposure to arachidonic acid was relatively low compared to omega-3 fats. The content of this diet is confirmed in human remains by carbon isotope analysis, in many areas ancient Atlantic coastal dwellers ate an almost exclusively seafood diet. Many cultures, such as Inuit, Norwegian, Japanese have continue to use cold water fish as a source of dietary fat until modern times. In Mesoamerica, the diet was rich in plant sources (no arachidonic acid), fish, insects and very little range-fed animals. The midden studies from the Americas suggest that shellfish and fish consumption was a common diet in coastal, river and lake cultures. Cooperative agriculture of squash, corn and beans supplemented with fish, animals or insects in many areas allowed increased populations without domesticated grazers. Certain squash seeds, like pumpkin seeds are high in omega-3 fats. In cultures that took wild game, the parts of animals less preferred in western culture, the eyes and brains, for instance, have high levels of biologically useful omega-3 fats. Therefore prehistoric and historic precedences demostrate the peoples strove to increase omega-3 fats within the diet and rich arachidonate sources may have been uncommon for many peoples.

The adaptation of peoples to low arachidonate or high omega-3 fat containing diets may have selected for more new production in the body and less down-regulation of high levels. In areas of the world such as central and Eastern Europe, Middle East, Central Asia and parts of South Asia, were the intake of range-fed or wild bovids was high, tolerance for dietary w6A may have been higher. Worldwide there has been an increase in the new millennium of affluent foods, particularly beef, this increase in consumption in peoples susceptible to inflammatory diseases may be a factor in sensitivity. This coupled with other genetic factors, such as HLA antigens, diabetes predispositions in sedentary or cereal eating societies may be additional risk factors.