Thursday, June 20, 2013

PUFA, Lipid Peroxidation Processes, and the Implications for Atherosclerosis and Diet Part III

Part I, II

Out of curiosity, using cronometer, I decided to see how much PUFA I was eating on a daily basis for a week.  It was tedious but, on average, I had consumed about 5 grams of PUFA a day, and substantially greater amounts of monounsaturated and saturated fats.  An essential fatty acid (EFA) deficiency is out of the question at this level, at least per the clinicial signs and symptoms, but I naturally began to wonder what my tissues would look like if I had been consuming much less PUFA, essentially depleting myself of linoleic acid (LA) and arachidonic acid (AA). 
It turns out that the synthesis and presence of eicosatrienoic acid (ETA), or mead acid, would increase, in proportion to the exclusion of the EFAs from the diet, and the appearance of ETA can occur in a matter of days.  You’ll seldom find information on ETA in textbooks and in searches on databases that index scientific articles, like PubMed, other than the fact that it serves as a marker for an EFA deficiency.  The mere presence of ETA is also usually taken as evidence that an EFA deficiency has caused, or contributed, to the condition that tends to coexist with it. 

But an EFA deficiency per se is not always at play, as there could be an inability to synthesize and desaturate fatty acids properly, in which case the addition of PUFA would probably provide benefit. (PUFA have indispensable signaling and structural functions, namely in the phospholipids that are found in cell membranes.)  Or, it could merely indicate an overall poor diet.

Despite what's typically said to the contrary, saturated fatty acids are critical components of phospholipids, not merely of triglycerides, as well, and the importance of this is seen no more dramatically than in the lungs.

Normally, phospholipids bear one PUFA molecule and one saturated fatty acid (SFA) molecule, but the lungs are unique in that they incorporate two molecules of palmitic acid.  The reason for this is simple: Phospholipids with straight-chain fatty acids pack neatly into small spaces when the lungs deflate and readily spread out when the lungs inflate, acting as “anti-glue” of sorts (or technically, as surfactants).  So the replacement of a PUFA molecule for a SFA molecule permits the lungs to inflate properly with only modest increases in air pressure, thereby decreasing the amount of muscular work needed to breathe.  The loss or replacement of a SFA molecule for a PUFA molecule would be catastrophic, especially in neonates whose lungs don’t develop fully until just before birth.

In enzymatic processes, PUFA that can bend into a tight hairpin shape, so as to facilitate the formation of a ring structure, can be oxidized to a host of messenger molecules collectively called eicosanoids.  So, cis oriented PUFA can participate in these reactions, whereas trans oriented PUFA can’t, which explains why trans fatty acids are more resistant to enzymatic (and nonenzymatic) peroxidation processes, and thus not likely to lead to inflammation (and oxidative stress) like other PUFA.1 (The alarmism and the pleading, in sepulchral tones, to avoid trans fatty acids at all costs, at least thus far, is unfounded and gross.  Ew.)
Besides arachidonic acid (AA), other 20-carbon PUFA, including eicosapentaenoic acid (EPA), an omega-3 fatty acid, and ETA, an omega-9 fatty acid, can form their own series of eicosanoids.

The range of processes that these eicosanoids are involved in are too numerous to list here, but I want to call attention to the idea that the eicosanoids (prostaglandins, thromboxanes, and leukotrienes) have effects in the body that are contingent on the starting PUFA from which they're derived, and this is governed, for all intents and purposes, by the relative amounts of AA, EPA, and ETA present in our tissues.
The addition of ETA, for instance, increased the percentage of ETA in the tissues and organs of rats in proportion to the percentage of linoleic acid (LA) in their diets, and the presence of ETA inhibited the production of leukotriene-B4, which is highly inflammatory and implicated in many diseases.2 (Credit goes to Dr.Ray Peat, via an email exchange, for making me aware of this.)  Similarly, the addition of EPA, a major fatty acid in fish oil, decreases the generation of leukotriene-B4, but probably by way of a slightly different mechanism.3 

Nonetheless, the enzymes that generate the leukotrienes are the same enzymes that generate free radicals and a host of PUFA peroxidation products that oxidize LDL particles and are involved early on in atherosclerosis.4,5  ETA is chemically more stable than EPA, so could serve the purpose of curtailing the production of the inflammatory leukotriene-B4, among the other eicosanoids, in a safer way. (Though, whether this approach is as rationale in practice as it is in theory has yet to be properly tested and decided on.)

The liberation of PUFA is accompanied by the depletion of ATP, through its conversion to cAMP, and low levels of ATP accelerate lipid peroxidation processes.  Further, cardiolipin, which interacts with the proteins of the inner mitochondrial respiratory chain (especially those of complexes I, III, and IV),6 become more unsaturated with aging, and this is one way by which the cardiolipin content in cells can decrease, resulting in a decreased efficiency of ATP generation.  (In one animal study, the presence of docosahexaenoic acid [DHA] in cardiolipin was significantly associated with oxygen wasting, whereas the presence of palmitoleic acid was inversely associated with oxygen wasting.7)  So, the higher the cardiolipin saturation index, already relatively resistant to peroxidation, the more ATP would be produced, and this in turn would provide further protection against peroxidation processes.8

As an aside, thyroid hormone induces cardiolipin biosynthesis, but at the same time reduces the saturation index therein, favoring AA to LA, rendering cardiolipin more susceptible to lipid peroxidation processes.  Totally in line with this, in hyperthyroidism there is appreciable amounts of oxygen wasting.

In summary, in the absence or deficiency of one type of PUFA, another can stand in its place as storage triglycerides, structural elements in phospholipids, and substrates for enzymatic processes.  The omega-9 series, of which ETA is a member, are anti-inflammatory like the corresponding members of the omega-3 series are, but are more resistant to lipid peroxidation processes, the products of which are linked to the development of cardiovascular disease.   As a rule, the lower the exposure to the EFAs, the greater the rate of ETA production (far exceeding the constitutive rates of ETA production in mammals), and the greater percentage of ETA will be present in tissues, which may be beneficial for inflammation and oxidative stress.  And finally, caloric restriction has been shown to decrease the activity of the desaturase enzymes, by slightly lowering thyroid and insulin levels, and this in turn helps to preserve, and to restore, the cardiolipin associated with youth.

1.        Smit, L. A., Katan, M. B., Wanders, A. J., Basu, S. & Brouwer, I. A. A high intake of trans fatty acids has little effect on markers of inflammation and oxidative stress in humans. The Journal of nutrition 141, 1673–8 (2011).
2.        Cleland, L. G. et al. Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid. The Journal of nutrition 126, 1534–40 (1996).
3.        James, M. J., Gibson, R. A., Neumann, M. A. & Cleland, L. G. Effect of dietary supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis. The Journal of experimental medicine 178, 2261–5 (1993).
4.        Kühn, H., Heydeck, D., Hugou, I. & Gniwotta, C. In vivo action of 15-lipoxygenase in early stages of human atherogenesis. The Journal of clinical investigation 99, 888–93 (1997).
5.        Takahashi, Y., Zhu, H. & Yoshimoto, T. Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis. Antioxidants & redox signaling 7, 425–31
6.        Chicco, A. J. & Sparagna, G. C. Role of cardiolipin alterations in mitochondrial dysfunction and disease. American journal of physiology. Cell physiology 292, C33–44 (2007).
7.        Dumas, J.-F. et al. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. Journal of hepatology 54, 320–7 (2011).
8.        Paradies, G. et al. Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free radical biology & medicine 27, 42–50 (1999).