This topic deserves its own thread. I want to add to what MR said in the other thread (please DO read his terrific post first) and continue the discussion here.
To repeat:
People tend to forget just how complex the whole issue is when they turn to simplifications like "PUFA increases oxLDL, therefore it must be unhealthy")
Long ago this was meant as a follow-up to my post about the complexities of Lp(a) metabolism, but I will probably never get around to finishing the post. So here are my "notes" about the issue.
What follows is a ranting, geeky and most of all unpolished post.
Now oxidative stress in general and oxidative modification of LDL in specific is a difficult issue and I am only going to scratch the surface of this topic. I tried to review the studies that presumably show PUFA, esp. n6, to increase 1. oxLDL, 2. oxidative stress and 3. inflammation (here I relied mostly on secondary sources)
First, it bears repeating that MUFA can give you an improved TC/HDL ratio (not offset by Lpa) w/o any oxidation-related issues. The following only applies to PUFA alone and vs SAFA.
Before arriving at a conclusion we must carefully consider the limitations of current research:
a. research is still in its infancy; there are no meta-analyses, only few and somewhat limited prospective studies - this applies to oxidative stress and oxLDL measurements
b. oxLDL (measured as oxPl/ApoB via the E06 assay) is highly correlated with Lp(a) and not an independent risk marker in several studies
c. because none of the current assays directly measure oxLDL in situ (the artery wall) causality remains unclear, even more so than for Lp(a)
In vitro MUFA protects LDL from copper-induced oxidation, PUFA and SAFA are *both* worse. (MUFA >> safa > or = pufa see e.g. [Mata et al. 1, Lapointe et al. 2])
Notably, this was demonstrated using high-oleic sunflower oil not EVOO [?Lapointe et al. 2?]. But let us disregard this assay, which is commonly and understandably considered unphysiologic.
Only few studies to date used reliable markers of oxLDL in vivo
I was surprised myself that I could not find many actually useful papers while everyone kept repeating "PUFA raises oxLDL!" Was it all based on flimsy in vitro data?
One of the few studies assessing the effect of PUFA on in vivo oxLDL used the E06 assay (Silaste et al. 2004 [3]).
Another one used the Mercodia assay, but found no changes [Damsgaard et al. 2008, 4]. Some studies looked at MDA-LDL and many assessed other circulating markers of ox. stress - all of which have their limitations.
Even the best available markers seem to be mediocre [5]:
"F2-Isoprostanes, derived from non-enzymatic free-radical-mediated peroxidation of arachidonic acid, are arguably the best established biomarker of oxidative stress...Despite noting the expected associations between several established CHD risk factors and CHD events, no significant link was observed between measured oxidation markers ["markers of lipid (F2-isoprostanes) and protein (oxidized apoA-I) oxidation"] and CHD risk, a finding which further challenges the oxidation hypothesis for CHD."
Returning to Silaste et al [3]., they found increased OxLDL-EO6 titers but the assay in fact could be measuring beneficial efflux of oxLDL:
"The correlation between OxLDL-EO6 and Lp(a) was as high as 0.97 (P<0.001). Therefore, we suggest that the most likely reason for the increase in OxLDL-EO6 in response to the diets was that the Lp(a) levels increased. If Lp(a) acts as a plasma transporter of oxidized phospholipids, it can be hypothesized that both low-fat diets resulted in favorable changes in the artery wall or other tissues that decreased oxidation. Increased Lp(a) would result in increased transport of oxidized phospholipid away from tissues, such as the artery wall"
It would be circular to rely on the dietary studies themselves as evidence of PUFA safety, but the fact that known anti-atherogenic therapies increase oxPl/apoB (and perhaps Lp(a)) in humans (statins!) and animals strongly suggests that these markers either reflect efflux or are weak enough to be offset by lipid lowering or other pleiotropic effects [6].
„All studies performed to date with low-fat vegetarian or step II American Heart Association diet, or different doses and different types of statins [!], show an increase rather than a decrease in OxPL/apoB, along with a concomitant increase in Lp(a) (49). Although the mechanistic underpinnings of this observation are not fully determined, dietary atherosclerosis regression studies in animals with or without Lp(a) have shown similar increases in OxPL/apoB [=E06 assay] and, importantly, with concomitant removal of OxPL from atherosclerotic lesions (49). This suggests the hypothesis that mobilization of OxPL from the vessel wall or other inflammatory sites and transfer to lipoproteins, and particularly Lp(a) in humans, may occur during atherosclerosis regression.”
Even if we were sure that both Lp(a) and oxLDL reflect causal pathogenic processes, they do not have to be additive. Conceivably, Lp(a) may increase as an (adaptive) response to oxLDL or vice versa.
In short, it is not clear that the increases in oxLDL measured, if any exist, are causally linked to CVD - either at all or because they mirror Lp(a) or because they are easily offset. If they were, it would be almost impossible to quantify their effects right now due to a paucity of prospective studies.
Instead we better rely more on established risk markers and outcome studies rather than speculative evidence (see below).
Lastly, why should we single out oxLDL as THE marker?
If we honestly want to understand the effects of PUFA we should look into all markers of oxidative stress and inflammation. And this is still an unresolved issue. Note that, counterintuitively, there is not much evidence showing n6 or n3 PUFA to be pro-inflammatory (but see for a review [7, 8]).
When it comes to oxidative stress every single study looking at small increases in PUFA (often n6 rich) finds no or only minimal increases in markers of ox. stress. I do not think the results are all necessary an artifact of statistical power - i.e. a harmful effect too small to be measured reliably in such small studies - since at least two authors noted neutral and beneficial changes in some markers (Turpeinen et al 1995 [9], Sarkkinen et al. 1993 [10]) (note that I could not access and read [10] in full)
However, even if the small increases in ox. stress are real - and I think they are - then, potential risks still must be balanced against possible benefits like LDL/HDL lowering and more freedom with your dietary habits. (=this ends up with mechanistic vs mechanistic evidence, clinical & endpoint data is what matters, see below).
Conclusion - a reappraisal, clinical evidence, evidence from long-lived rodents
Based on the CVD, cancer and animal data I have seen [11-15, and others] this puts the UL for PUFA at around ~8%* or more in healthy males, those are intake levels that have been shown to posses (almost) no pro-oxidative effects and are well-studied (RCTs, epi).
Whatever the established UL for men, women would want to stay somewhat lower: 1. they have lower absolute CVD risk, 2. different metabolism of PUFA & differential tox. (not cited), 3. slightly higher avg. and max. life spans and thus more time for rare side-effects and effects on aging per se to show up
The evidence against n6 PUFA from RCTs and epi studies is not convincing despite the probable use of partially pre-oxidised oils (improper storage, cooking w/ hiPUFA oils) and potentially sub-optimal antioxidant and vitamin status in the studied populations and a notoriously low N3 intake (not necessarily skewed n3/n6 balance, just flat out low n3).
OTOH, evidence in favour of PUFA is not robust either, but MUFA-rich foods (w/ modest not low PUFA content) are better supported by the evidence, i.e. EVOO and nuts.
Most of this conclusion was written before Ramsden et al. [11] and for the sake of intellectual honesty (and some laziness) I am publishing it anyway. However, I do not think the paper changes that much, since their findings are consistent with both major hypotheses:
1. n3 good, n6 toxic 2. n6 neutral/benefical together with n3. I am now even more cautious and weary of PUFAs than before but this is far from supporting all the anti-PUFA hysteria we get from some people and some popular blogs 'n authors.
And it does not change "my" basic recommendations, in which I wholeheartedly second Mich*ae1: eat mostly MUFA- & polyphenol-rich foods that have a track record in clinical studies, i.e. nuts and EVOO, and ignore their PUFA content.
So why again should we care about mechanistic speculation based on inconclusive in vitro, animal data and surrogates at all if we have outcome data? [Jakobsen et al. 11, Mozaffarian et al. 12, also read Katan & Zock's brilliant cancer review 14, Ramsden et al. op. cit.]
Neither the CVD nor the cancer epidemiology indicts PUFA...
One counter argument is that the studies on hard endpoints are too short to demonstrate long-term efficacy and safety. Another is based on the (mitochondrial) free radical theory of aging and worrying long term feeding data - which I so want to fully review in more detail.** All interesting questions. And I would not call the case closed yet.
Addendum:
It seems, a recent MAJOR publication makes a very strong case against the (mitochondrial) oxidative stress theory of aging, its modern membrane fatty acid peroxidation incarnation, and attests to the long term safety of PUFA in mus musculus and in a decently long lived strain at that [15]. Please discuss in this thread.
For a general review of ox. stress and aging see [16].
*this is just a rough first guess since people always like to put numbers to an idea
**I read many papers but I have never been sure why you "discounted" the data almost completely, MR, esp. if you subscribe to the DHA-accelerated hypothesis of aging (for CRONies)? I am talking mostly about Quiles et al., their short lived little rodents, and studies demonstrating increased peroxidation index after PUFA feeding (I think even after n6, not only n3, but I might misremember).
After [15] has been published my opinion has changed somewhat..
[1] Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2088-95.
Monounsaturated and polyunsaturated n-6 fatty acid-enriched diets modify LDL oxidation and decrease human coronary smooth muscle cell DNA synthesis. Mata et al.
http://atvb.ahajourn...full/17/10/2088
[2] J Nutr Biochem. 2006 Oct;17(10):645-58. Epub 2006 Feb 3.
Effects of dietary factors on oxidation of low-density lipoprotein particles.
Lapointe et al.
[3] Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):498-503. Epub 2004 Jan 22.
Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a). Silaste et al.
http://atvb.ahajourn...t/full/24/3/498
[4] J Nutr. 2008 Jun;138(6):1061-6.
Fish oil in combination with high or low intakes of linoleic acid lowers plasma triacylglycerols but does not affect other cardiovascular risk markers in healthy men.
Damsgaard CT, Frøkiaer H, Andersen AD, Lauritzen L.
http://jn.nutrition....full/138/6/1061
[5] Clin Sci (Lond). 2009 Jan;116(1):53-60.
Association between both lipid and protein oxidation and the risk of fatal or non-fatal coronary heart disease in a human population.
http://www.clinsci.o...3/cs1160053.htm
[6] J Lipid Res. 2009 Apr;50 Suppl:S207-12. Epub 2008 Dec 4.
The role of oxidized phospholipids in atherosclerosis.
Berliner JA, Leitinger N, Tsimikas S.
http://www.jlr.org/c...ement/S207.full
[7] Circulation. 2009 Feb 17;119(6):902-7. Epub 2009 Jan 26.
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.
Harris et al.
[8] Curr Atheroscler Rep. 2006 Nov;8(6):453-9.
The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses.
Harris WS.
[9] Sarkkinen, E.S., Uusitupa, M.I.J., Nyyss6nen, K., Parviainen, M., Penttil~i, I., Salonen, J.T. (1993) Eur. J. Clin. Nutr. 47, 623-630.
[10]Lipids. 1995 Jun;30(6):485-92.
Plasma and lipoprotein lipid peroxidation in humans on sunflower and rapeseed oil diets.
Turpeinen AM, Alfthan G, Valsta L, Hietanen E, Salonen JT, Schunk H, Nyyssönen K, Mutanen M.
[11] Br J Nutr. 2010 Dec;104(11):1586-600.
n-6 Fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials.
Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM.
[12] Mozaffarian D, Micha R, Wallace S (2010) Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS Med 7(3): e1000252. doi:10.1371/journal.pmed.1000252
http://clinicaltrial...al.pmed.1000252
[13] Am J Clin Nutr. 2009 May;89(5):1425-32. Epub 2009 Feb 11.
Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Jakobsen et al.
http://www.ajcn.org/.../full/89/5/1425
[14] Zock PL, Katan MB. Linoleic acid intake and cancer risk: a review and meta-analysis. Am J Clin Nutr. 1998; 68: 142–153
[15] J Comp Physiol B. 2011 Feb;181(2):289-98. Epub 2010 Oct 28.
Feeding into old age: long-term effects of dietary fatty acid supplementation on tissue composition and life span in mice.
Valencak TG, Ruf T.
[16] Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging?
Salmon AB, Richardson A, Pérez VI.
Free Radic Biol Med. 2010 Mar 1;48(5):642-55. Epub 2009 Dec 28. Review.
http://www.ncbi.nlm....95/?tool=pubmed
Biochim Biophys Acta. 2009 Oct;1790(10):1005-14. Epub 2009 Jun 11.
Is the oxidative stress theory of aging dead?
Pérez VI, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y, Richardson A.
http://www.ncbi.nlm....32/?tool=pubmed
Edited by kismet, 29 April 2011 - 06:02 PM.
