Friday, April 5, 2013

PUFA, lipid peroxidation processes, and the implications for atherosclerosis and diet

I recently read on the interwebz that fish oil lowers triglyceride levels in the blood by depositing them in the arteries.  I have known about this triglyceride lowering effect, and whether I should be taking fish oil as a supplement as is recommended by major health organizations, alternative health practitioners, and my mom. 

As a whole, I think the clinical trial evidence for fish oil for the prevention and treatment of cardiovascular disease, especially of late, have been disappointing, to say the least, and this goes for the other conditions for which fish oil has been, for years now, said to benefit.  Fish oil does in reality lower triglycerides but what is the trade-off? 

Studies like this one by Angerer et al., for instance, in which subjects who were randomized to receive fish oil—1.65 grams of omega-3 fatty acids per day— or a placebo demonstrated, after two years, a greater degree of atherosclerosis in the carotid arteries of the subjects who had received fish oil compared to those who had received a placebo.1

The presence of highly reactive methylene groups renders PUFA highly susceptible to peroxidation processes, and the more double bonds a PUFA molecule has, the greater the chance becomes.  As an example, DHA and EPA are more susceptible than arachidonic acid (AA), which are both more susceptible than linoleic acid (LA) and alpha linolenic acid (ALA) to lipid peroxidation processes.

PUFA can peroxidize and decompose in the blood and in cell membranes (in which they're found in phospholipids), though they're probably protected more in the membranes than in the blood.2 A certain amount of PUFA in membranes seems to be needed for physical and signaling purposes.

The accumulation of AGE and PUFA decomposition products, namely those derived from LA and AA, are potent risk factors for cardiovascular disease.  Although I don’t think omega-3 fatty acids are necessarily deleterious in any and all amounts, I do think that with respect to the previously mentioned cardiovascular risk factors, we should regard omega-3 fatty acids no differently as we do omega-6 fatty acids, as all PUFA, because of the presence of said reactive methylene groups, can undergo peroxidation processes. (Funnily, omega-3 fatty acids are the worst in this regard.)

The LDL particle contains a large “lipid core” composed primarily of cholesterol esters.  A cholesterol ester is composed of a cholesterol molecule that is attached to a fatty acid molecule, the identity of which is determined, primarily, by the types of fats and oils we eat.  In humans, the predominate fatty acid present in cholesterol esters is LA3
; herein is where the action lies.

Each component of the cholesterol ester can undergo oxidation reactions: Cholesterol tends to form epoxides, whereas LA is further oxidized to hydroxyoctadecadienoic acid (HODE).  HODE itself is a potent promoter of inflammation, activator of PPAR-γ, and stimulator of IL-1β release from white blood cells.

HODE bearing LDL particles can be taken up, via LDL receptors, into cells, thereby initiating degenerative processes therein.  Oxidative processes such as these accumulate in vascular tissue with aging.  This is clear.  If LA, whose only source is our diets, is the principle source of oxidative products in LDL particles, then the recommendation to replace saturated fats — which can’t be oxidized like PUFA can — for LA containing oils may have been worse than it has been recently described.4 

Although cholesterol can oxidize and decompose to toxic byproducts, oxidized LA is much more abundant than oxidized cholesterol is in LDL particles, so the focus on cholesterol by major health organizations is probably misplaced.  Simply put, oxidized LDL is toxic, and the PUFA, not the cholesterol, found therein is what is predominantly oxidized.  LA and its oxidation products predominate in atherosclerotic plaques as determined by analyses of samples of these plaques with HPLC followed by gas chromatography techniques.6 (Palmitate, surprisingly, is found in nearly equally high amounts.)

The LA peroxidation products can also glycate the lysine residues found in the LDL particle itself, namely apolipoprotein E, a protein whose function is to bind to the LDL receptor.  In the absence of functional apolipoprotein E, LDL particles are instead taken up by white blood cells (macrophages), which take up modified LDL particles, seemingly without limit, after which they are ultimately deposited as plaques in the arteries.5

Across taxa, the membrane peroxidizability index correlates with maximum lifespan years.7 This has been proposed as the main mechanism by which caloric restriction extends lifespan8, and is probably due to the slight decrease in thyroid hormone and insulin levels in the blood of those who embark on eating less food, as insulin and thyroid hormone modulate the activity of the desaturase enzymes.  In mice, this is associated with mitochondrial synthesis and an increased production of ATP.9 

Although I try to keep PUFA in my diet as low as possible, I will, every so often, eat a fat slab of oily fish, a handful of cashews, and even junk food that contains seed oils.  I don’t think it’s necessary to avoid these foods because of the presence of small amounts of PUFA in them as there are other factors in our diets that counteract their potentially harmful effects.  Also, the composition of fats we eat is not the sole determinant of our susceptibility to lipid peroxidation processes. And on top of that, we have the ability to remove these toxic lipid peroxidation products after they form.  So stressing about consuming a small amount of PUFA would be kind of, sort of, neurotic.

It should be borne in mind that the studies in which omega-3 fatty acids have been shown to be either ineffective or harmful employ omega-3 fatty acid supplements. . . . I think there is a good possibility that omega-3 fatty acid containing foods would have a different effect, and I don't think there is enough cause to rigorously avoid them.


1.       Angerer, P., Kothny, W., Störk, S. & Von Schacky, C. Effect of dietary supplementation with omega-3 fatty acids on progression of atherosclerosis in carotid arteries. Cardiovascular research 54, 183–90 (2002).
2.       Spiteller, P., Kern, W., Reiner, J. & Spiteller, G. Aldehydic lipid peroxidation products derived from linoleic acid. Biochimica et biophysica acta 1531, 188–208 (2001).
3.       Berg, J. M., Tymoczko, J. L. & Stryer, L. Biochemistry. 1026 (W. H. Freeman: 2006).
4.       Ramsden, C. E. et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ (Clinical research ed.) 346, e8707 (2013).
5.       Steinbrecher, U. P. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. The Journal of biological chemistry 262, 3603–8 (1987).
6.       Waddington, E., Sienuarine, K., Puddey, I. & Croft, K. Identification and quantitation of unique fatty acid oxidation products in human atherosclerotic plaque using high-performance liquid chromatography. Analytical biochemistry 292, 234–44 (2001).
7.       Pamplona, R. et al. Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals. Journal of lipid research 39, 1989–94 (1998).
8.       Hulbert, a J. Metabolism and longevity: is there a role for membrane fatty acids? Integrative and comparative biology 50, 808–17 (2010).
9.       Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science (New York, N.Y.) 310, 314–7 (2005).