So now lets get to the part about why PUFAs are so bad.
The predominant omega 6 fatty acid is arachidonic acid (AA), which can be reduced (i) via enzymatic peroxidation to prostaglandins, leukotrienes, thromboxanes, and other cyclooxygenase, lipoxygenase or cytochrome P-450 derived products or (ii) via nonenzymatic peroxidation to MDA, 4-HNE, isoprostanes, and other lipid peroxidation end-products (more stables and toxic than hydroperoxides) through oxygen radical-dependent oxidative routes.
As mentioned in Part 1, the lone hydrogen between two doubles makes the PUFA very susceptible to an attack from a free radical (as shown by point number 7 in the first picture of part 1). That hydrogen is stolen by a free radical, such as OH· and HOO·, to form water, and a fatty acid radical. This fatty acid radical then reacts with another non-radical free fatty acid, producing a different fatty acid radical and a lipid peroxidation product (radicals, lipid hydroperoxides, and reactive aldehyde derivatives).
Lipid peroxides of omega 3 (α-linolenic acid and docosahexaenoic acid) generate 4-hydroxy-2-hexenal (HHE), which is a potential mediator of mitochondrial permeability transition. Lipid peroxides of omega 6 (linoleic and arachidonic acid) generate 4-hydroxy-2-nonenal (HNE).
Other lipid peroxides (aldehydes) include malondialdehyde (MDA), 4-hydroxynonenal (HNE), glyoxals, acrolein, etc., which are toxic, contribute to lipofuscin formation, create glycation products, inhibit cholesterol synthesis (lecithin:cholesterol acyltransferase), are immunosuppressive, cause neurodegeneration, cardiovascular disease (increase LDL and oxidized LDL), liver fibrosis, promote inflammation by increasing COX, and increase the risk of cancer, as well as contribute to a variety of other diseases. (1, 2, 3, 4)
PUFAs, and not SFAs or MUFAs, create protein carbonyl groups, and high levels of these proteins have been observed in Alzheimer’s disease (AD), rheumatoid arthritis, diabetes, sepsis, chronic renal failure, and respiratory distress syndrome. (5)
Lipid peroxidation-derived aldehydes can also easily diffuse across membranes and can damage any protein in the cytoplasm and nucleus, far from their site of origin, making it a whole body danger, and not just locally where it is produced. (6)
The body is constantly busy putting amino acids together to structure proteins which serve various roles, such as enzymes, transporters, receptors, etc. Lipid peroxides damage these proteins and alter their function, preventing them from working as they should. Luckily the body is able to re-fold them into their proper shape, however, PUFAs also inhibit these specific enzymes from doing so, allowing damaged proteins to build up in the body, leading to major problems and diseases, as mentioned earlier.
As long as there is a radical lipid, it can cause a chain reaction and continual lipid peroxide formation, unless the lipid radical is quenched by an anti-oxidant such as vitamin E. So anything that is or can make free radicals, such as nitric oxide, iron, TCA cycle, ionizing radiation, ultraviolet rays, tobacco smoke, pathogen infections, environmental toxins, herbicide/insecticides, etc., can damage PUFAs and cause lipid peroxides to be formed.
Lipid peroxidation is when a PUFA reacts with a free radical in the body and forms a lipid peroxide, which is toxic to the body.
Prostaglandins (PGs) and leukotrienes
Certain enzymes, such as phospholipase C and A2, cleave the arachidonic acid from phospholipids, and is then used by the cyclooxygenase (COX) and lipooxygenase (LOX) pathways. The COX enzyme produces thromboxane, prostacyclin and prostaglandin D, E and F. The LOX enzyme pathway synthesizes leukotrienes. These bi-products from COX and LOX cause inflammation, thrombosis (thromboxanes), high blood pressure, allergies, immune responses, fevers, cancer growth, pain sensation, asthma (leukotrienes), and much more.
The preferred substrates of COX must contain at least three double bonds, and these precursor fatty acids are dihomo-γ-linolenic, arachidonic, and eicosapentaenoic (EPA) acids, which contain 3, 4, and 5 double bonds, respectively. Other fatty acids lacking the three double bonds in the required positions can be oxygenated by COX to hydroperoxy fatty acids, but not to PGs. Mead acid (C20:3n-9) is transformed to 13-hydroxy-5,8,11-eicosatrienoic acid by COX-1 and cannot become a prostaglandin. (8)
- Linoleic acid → γ-linolenic acid → dihomo-γ-linolenic acid → arachidonic acid.
- α-linolenic acid → eicosapentaenoic.
Dihomo-γ-linolenic acid creates the 1 series prostaglandins (PGE1), arachidonic acid creates PGE2 and EPA creates PGE3. Although PGE1 and PGE2 are about the same strength in terms of causing damage, PGE1 from EPA is far less powerful and dangerous as it’s only about a ¹⁄₄ the activity of prostaglandin E2. These three fatty acids interact with peroxynitrate (ONOO−) through the COX enzyme to form a prostaglandin and a nitric oxide (NO).
- Dihomo-γ-linolenic acid + ONOO− ⟶ COX ⟶ 1-series prostaglandins + NO.
- Arachidonic acid + ONOO−⟶ COX ⟶ 2-series prostaglandins + NO.
- Eicosapentaenoic acid + ONOO− ⟶ COX ⟶ 3-series prostaglandins + NO.
Furthermore, arachidonic acid also creates thromboxane A2 (TXA2) and the 4-series leukotrienes (LTB4), which are highly active agents of inflammation. Whereas EPA creates thromboxane A3 (TXA3) and the 5-series leukotrienes (LTB5), which are 10 times less potent than LTB4 (9). Mead acid creates the 3-series leukotrienes (LTB3) which are also much less potent than the 4 series.
Prostaglandins increase COX activity (thus increasing it’s own synthesis, PGE2 4-fold stronger than PGE3), upregulate ornithine decarboxylase (which increase polyamine synthesis and excessive polyamines contributes to cancerous growth), activate PPARγ (which is involved in hibernation and increased fat storage), pathologically stimulate growth (PGE2), induce hypoxia (stimulate hypoxia inducible factor), contribute to hairloss (PGD2), stimulate inflammation (cytokines such as IL1, IL6, TNFa, etc.), feed candida (candida produces PGE2 from arachidonic acid), cause vascular permeability, prostate cancer (men in the highest quartile of linoleic acid consumption had as much as a 5-fold increased risk of prostate cancer compared to men with low levels of consumption), contribute to degenerative diseases (10, 11, 12) and the list goes on.
In PUFA Dangers Part 3 we will be discussing the damage it does in the brain and it’s influence on dopamine, serotonin etc.