Lipid Hypothesis 2.0: Eat Butter

The original lipid hypothesis stated, more or less, that lowering blood cholesterol would reduce premature mortality from heart disease.  At the time, it was thought that dietary cholesterol and saturated fat increased the ‘bad’ type of blood cholesterol, so the advice was to restrict those foods.  All of that was wrong.

Time

Lipid Hypothesis 2.0: Eat Butter

In the revised version, it’s not total cholesterol, but rather the lipoprotein particle size and number that might matter.  At any given total level of cholesterol in the blood, the cholesterol can be found in a small number of big lipoproteins or a big number of small lipoproteins (it’s more like a spectrum)… and it seems like the former is the more favorable scenario.

The original lipid hypothesis was wrong about the impact of butter and eggs on cholesterol and CVD, but it may be right about their impact on lipoproteins… and it appears to be in the opposite direction predicted by the original hypothesis.

lipoprotein subclasses

That is, eating a diet rich in saturated fat and cholesterol, and low in carbohydrates, is associated with fewer and larger LDL particles.

Could history be repeating itself?  We know particle size and number is associated with disease risk, and we know diet can influence these characteristics.  Is it safe to assume lipoproteins that have been intentionally manipulated via diet carry the same risk associations as those naturally occurring?  Are they causal?

For a more comprehensive review of this topic:
video by Dr. Thomas Dayspring aka Dr. Lipid
Cholesterol Clarity by Jimmy Moore
slide show or video by the Fat Emporer, Ivor Cummins
blog post by Franziska Spritzler, RD

Abbreviations:
LDL-C = total cholesterol concentration in the blood (mg/dL)
LDL-P = particle number (nM) = number of apoB-containing lipoprotein particles per volume of blood (in the fasted state)

Small LDL particles are associated with a higher particle number at any given level of total LDL cholesterol concentration.  Total LDL cholesterol has little association with CVD risk, and from the Framingham studies, we know that if total HDL-C is high, CVD is low regardless of LDL-C.  That was before particle sizes were routinely measured, but still seems relevant today.  Lastly, insulin resistance and a high number of small LDL particles seem to track together.  For more, see:

Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression…” (Williams et al., 2014)

Here’s where diet and lifestyle may come into play.

Obesity is associated with a higher number of smaller LDL particles (eg, “Pattern B,” Chandra and Rohatgi, 2014), and increased risk of premature mortality (www.google.com).  The Chandra study also showed it may be possible to increase HDL-P with exercise.

Klempel and Varady showed, among other things, that alternate day fasting (ADF)-induced weight loss was associated with increased average LDL particle size, due primarily to a reduction in the number of smaller LDL particles (Klempel et al., 2013).  The intermittent fasting protocol used was 25% intake on day 1, 125% on day 2, repeat. Confounded by weight loss?  Perhaps.

 

Hodge et al., 2009: “in men, total PUFA and n-6 dietary fat intake and BMI were associated with a more atherogenic NMR-LSP pattern; while in women dietary glycemic index and WHR demonstrated positive associations, and n-3 fat intake an inverse association.”

What’s not “PUFA and n-6 dietary fat?”  Saturated fat.
What’s not high “glycemic index?”  Low carb.

Ron Krauss has been on the forefront of this for a while: Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia (Krauss et al., 2006)

Krauss

They showed the separate benefits of carbohydrate-restriction and weight loss on the atherogenic LDL Pattern B (Pattern B = higher number of smaller LDL particles):

Pattern B

In this study, the ‘separate effect’ of saturated fat was a further shift toward Pattern A.

 

LeCheminant and colleagues (2010) showed something similar, comparing low carb vs. low fat: significantly increased “Mean LDL Size” in the low carb group after 9 months.  The number of smaller LDL particles increased, albeit statistically non-significantly, in the low fat group.  Mean LDL Size, or particle diameter, reflects both particle size and number; increased ‘Mean LDL Size’ can be due to a decrease in the number of smaller particles or an increase in the number of larger particles.

Ron Krauss’s group at it again in 2010, showed, among other things, after 9 weeks, oxidized LDL increased and the LDL particles shifted toward Pattern B in people following a low fat compared to a low carb diet (Faghihnia et al., 2010).

“As expected, the low fat diet significantly decreased mean LDL peak particle diameter from 262 to 257 Å. ”

In 2013, Blesso and colleagues showed that a diet containing eggs significantly increased mean LDL diameter compared to one containing yolk-free egg substitutes… the egg group was receiving over 500 mg more cholesterol per day than the egg substitute group (fyi, this had no effect on total cholesterol levels)… and all other parameters, HDL-C, triacylglycerols, insulin sensitivity, etc., all exhibited greater improvements after 12 weeks of eating whole eggs (in the context of a moderately-reduced carb diet, which was similar in both groups), despite similar weight loss.  Thus, it could be said that the reductions in caloric and carbohydrate intakes mediated the weight loss, but the added intakes of saturated fat, cholesterol, and possibly choline in the EGG group resulted in lipoprotein improvements.

egg

Reduction in dietary trans fat intake is associated with decreased LDL particle number in a primary prevention population (Garshick et al., 2014)

 

 

And who can forget the American Paradox?  Mozaffarian et al., 2004:

“In multivariate analyses, a higher saturated fat intake was associated with a smaller decline in mean minimal coronary diameter (P = 0.001) and less progression of coronary stenosis (P = 0.002) during follow-up… Carbohydrate intake was positively associated with atherosclerotic progression (P = 0.001), particularly when the glycemic index was high.”  

CIMT, coronary stenosis, and atherosclerotic progression are more meaningful measurements/outcomes than changes in lipoprotein size and number.  They are associations in this case, no doubt, but potentially very important ones.

And now time for the big disclaimer: is history repeating itself?  As with the original lipid hypothesis, the links between particle composition and disease outcomes are correlations.  The links between diet and particle composition appear causal, in this case, but it’s hard to say, at this point, if they’ll also be associated (causally) with reduced disease risk.  If so, is it due to the lipoprotein particles themselves? or due to some other diet-induced change, like in insulin sensitivity, inflammation, stability of lipid membranes, etc.

 

calories proper

 

Become a Patron!

 

 

Be Sociable, Share!
Share
  • Gerard Pinzone

    I read a while back that the association between particle size and atherosclerosis is a misnomer borne out of improper statistics: http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-v

    I’ve also heard the idea that small particles are more atheroscrotic because their smaller size allows them to get “stuck” in the arterial wall doesn’t pass the stink test since the difference in size is very slight. The perferred explanation is that the sdLDL particles are more prone to oxidation and it’s oxidized LDL that’s the culprit. This is what Igor Cummins presents in his video: https://www.youtube.com/watch?v=fuj6nxCDBZ0

    So, anyone have any insight which hypothesis has more evidence currently?

    • yeah, a lot of the stronger correlations I’ve seen are found with increased particle number, which, at any given level of total cholesterol, is negatively associated with particle size. sdLDL is strongly correlated with insulin resistance (Dayspring), and oxLDL with hyperglycemia (from Ivor Cummins, I think).

      as to the pathological mechanism… this is very hard to determine directly, experimentally! There are many confounding factors – insulin resistance and hyperglycemia, for example.

      • great post Bill, flowing with the thrust of the root cause river, even though there are many mechanistic bywaters that the researchers have paddled around in for decades! I am interested in locking down on particle number being directly causal as opposed to partially associative too….so next week or three that is the focus. btw Nigel on another post suggests that Krauss & Dreon spiked the high carb with 50% sugar – my full version of Krauss’ doesn’t define – do you have the carb breakdown showing 50% pure sugar anywhere?

        • Thanks, Ivor.

          In the 2010 Krauss study, the ratio of simple:complex carbs was 1:1 in both groups.

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952573/

          The difference in carbs was 45% vs. 65% of total kcals, so the difference in simple sugar intake wasn’t huge… on a 2000 kcal diet, this might amount to roughly ~115 vs. 165 grams per day?

          This aspect of their study was designed to control for the ratio of simple to complex carbs… not exactly ‘nefarious,’ in my opinion.

          • Having 50% of carbs as sugars is nefarious. A high-carb diet with 32.5% of energy from sugars is going to have a completely different effect on particle size compared to a high-carb diet of sweet potatoes.

            The methodology was rigged to make “carbohydrates” look bad.

          • rs711

            Isn’t your argument tantamount to saying fruit is nefarious but potatoes aren’t? Pray tell – how’d that work?

          • No. My beef is the repeated conflating by Krauss of sugars with carbohydrates. There are carbs, carbs, carbs, carbs and carbs. They all have different effects.

            Also, whole fruits as part of a mixed diet won’t provide anything close to 32.5% of total energy from sugars.

        • “I am interested in locking down on particle number being directly causal as opposed to partially associative too”–

          Good luck with that, probably as misguided as the idea that cholesterol itself is evil.

          My current analogy* for particle number is one of traffic and roads. If the roads in your city are narrow torn up and potholed and poorly maintained and badly signed with shitty traffic flow and fuckwit drivers etc then the number of cars on it is a huge issue. You’ll get away with a small number of cars as when there’s the inevitble crash the ambulances/maintenance crews can get in and fix without much issue apart from little room on the shoulder. But if you have way too many cars there are more crashes, and subsequent pile-ups, and the emergency services either can’t get there to fix it in time OR they themselves become part of the pile-up.

          Then imagine a marble-smooth nice wide freeway, well maintained at the first sign of a pothole, traffic is well directed and flows like beer at Schutzenfest, and the drivers are a bunch of Canadians. Sure, the occasional crash happens, but emergency services can get there quickly and easily and they have plenty of room to deal with the situation. In this case it doesn’t really matter if there’s only several hundred cars, or a couple thousand.

          So yeah to me particle number is strictly correlative, because discordance. You simply can’t find near 100% of the time it being there. High particle number in a super inflammatory environment – MURDER ON THE DANCE FLOOR. High particle number in a well oiled machine – STAYIN’ ALIVE.

          *subject to change if I hear better :p

          • no probs ash, like yer analogy; I was a bit devious when I said “locking down on it being directly causal”, as it’s currently very much in the null hypothesis arena in my mind, until find reasonable proof that it is indeed predominantly causal – which I suspect is not the case…….if you put a gun to my head I’d say partially causal, with the bigger, actionable root cause elsewhere – but need the data, and it’s tricky to pull together enough triangulation to be convinced….pity they wasted so much work on BS stuff over the decades – otherwise it would be over by now! ….will keep at it, but allocating sufficient time currently is a mite challenging……..!

          • We’ve got a few (shortened) lifetimes worth of wasted “science” trying to prove causality for… reasons.

            Here’s some seed ideas:

            –> http://www.tylervigen.com/

          • ha! posted on that site before thanks for reminder – hilarious stuff – all researchers should internalize the likes of this, and inoculate themselves against future corny correlative capers!

      • Particle number increases in proportion to LDL-c.
        Particle number decreases in proportion to particle volume. Particle volume is proportional to particle size cubed.

        • George

          So now, when my LDL goes down, I need to worry that it may just have shrunk?

          • See the Kaplan-Meier survival curves:-
            http://1.bp.blogspot.com/-ikyVEcsuAd8/U59ChVW6MiI/AAAAAAAAA24/1OBuJNYZ9pA/s1600/Kaplan-Meier+Survival+Curves+for+LDL.jpg

            If your LDL-P doesn’t change when your LDL-c goes down, your particle size goes down and your chance of survival gets worse.
            However…
            If your particle size doesn’t change when your LDL-c goes down, your LDL-P goes down and your chance of survival gets better.

          • Andrés

            Nigel Kinbrum said:

            See the Kaplan-Meier survival curves

            No, those are not the survival curves. They are the event free survival curves. As I have said both on Dr. Attia’s blog and on Franziska’s one (comments don’t seem to be directly linkable) evidence is not so clear cut about the any-cause mortality predictive power of LDL-P. If anyone knows some other study apart the one on NHANES III data (on apoB), please let us know.

            On the other hand and focusing only on Coronary Artery Disease (CAD) events, it is very enlightening to take a look at the case-control study within prospective EPIC-Norfolk cohort. Although they don’t give directly the Odds Ratio for neither smoking nor diabetes, they can be easily computed from Table 1: 157/155/((1003-157)/(1885-155)) = 2.07 for smokers and 61/30/((1003-61)/(1885-30)) = 4.00 for diabetics. Actually the EPIC-Norfolk researches have given us a lot of information about any-cause mortality (commented by Petro) in their cohort so we know that Odds Ratio for diabetics gets morphed in a much worse Relative Risk of 8.16 (Table 2) for cardiovascular-death (3.59 for any-cause death).

            Let’s say the Relative Risk of CAD for non-smokers and non-diabetics given by LDL-P levels is going to be the same than for smokers and/or diabetics. Guess what happens to the number needed to treat if you don’t smoke and keep blood glucose below 140 mg/dl at all times, both quite feasible without any medication if not following conventional advice long enough to having crashed your pancreas.

            It is so sad all that focusing on cholesterol when every MD should be pushing glucometers on every one of their patients instead.

          • Fair enough about event free survival curves. My bad.

            A diet high in carbs as Resistant Starch (RS) won’t make BG go over 140mg/dL (7.78mmol/L). How do you think the Kitavans managed to maintain such low blood glucose & insulin levels (50% insulin level compared to Swedes) on a diet of 70%E carbs & 20%E fats?

            They maintained insulin sensitivity by not over-eating & by being active. That’s the secret to having low blood glucose & insulin. High insulin sensitivity + lots of carbs as RS.

          • Andrés

            Nigel Kinbrum said:

            A diet high in carbs as Resistant Starch (RS) won’t make BG go over 140mg/dL (7.78mmol/L).

            As far as our body is concerned, resistant starch is (mostly) butyrate. Yes, that seems to promote a better insulin sensitivity and lower blood glucose in the next meal through signaling the liver. Nevertheless I wouldn’t take for granted that someone doesn’t have to neither check it by himself/herself nor perhaps restrict the rest of carbohydrates accordingly. No one should be content with population based strategies when you can check and choose your personal one.

            It seems to me that any natural strategy conquering a tight blood glucose control should bring up a similar benefit.

          • I agree.
            People with type 2 diabetes should test their postprandial blood glucose, to be on the safe side.
            As for people with impaired glucose tolerance, I don’t know if testing is necessary.

          • rs711

            “lots of carbs as RS” ==> translation: not actually having lots of carbs….as, RS is unavailable glucose functioning as a fiber providing butyric acid energy to colonocytes but no significant amount of energy useable elsewhere in the body.

            We don’t have much data about the amount of RS or other fibers in their diet from Lindbergs papers.

            I don’t think we know the answer to how a high available-glucose diet (as far as we can tell) allows health in Kitavans. You’re right that activity likely plays a significant role.

            “not overeating” doesn’t tell us WHY they don’t but we do tend to (on high carb diets) in the ‘west’.

          • “high carb diets” in the west usually means refined sugars & starches e.g. stuff made out of grain dust.

            The term “wholegrain” has become corrupted to include grains that have been turned into dust. The whole grain is present, but the grain is no longer “whole” i.e. intact.

            Recognisably whole grains are fine e.g. rolled & puffed wheat, boiled & puffed rice, rolled oats etc. See also http://nigeepoo.blogspot.co.uk/2010/02/problem-with-whole-grain-cereals.html

          • rs711

            It’s irrelevant that “wholegrains” are made into dust because humans simply cannot otherwise use them as a means for gaining energy or micronutrients anyways.

            They have to be processed. You’re simply drawing the line where it fits with you preconceptions.

            I do not doubt that sweet potatoes can be filling. Actually, having eaten quite a few, I’d tend to agree. So what?

          • Muesli & porridge use rolled grains. Also Puffed wheat & rice are digestible and don’t disturb BG like flour does. What are you talking about – have to be processed? They don’t have to be turned into dust.

          • rs711

            “Also Puffed wheat & rice are digestible and don’t disturb BG like flour does” —> I see it never gets old to compare things in order to saying the least harmful one is somehow actually ‘good’ or ‘OK’.

            White rice is at best a toxin-free micronutrient-poor pure of glucose source. Ain’t so bad in the grand scheme of things.
            Brown rice is a hulled grain, meaning it has its defences up & won’t play kindly with your gut – remember, if it rhymes it must be true!

            I say – we’re devilishly clever apex predators and we should eat like one. Desperate ones eat grains and only silly ones think they should make a point of eating them.

          • for what it’s worth, studies on low glycemic index diets in metabolic syndrome aren’t particularly compelling… ie, I don’t think switching white rice for brown rice will have much of an impact

          • Whatever. If it’s not good for you, don’t eat it.

            Just don’t presume that what’s not good for you is not good for everyone else.

            I’m done here. Bye.

          • Yeah, I love hearing folk tout the amazingness of olive oil – it’s #1 benefit by far is that it displaces a lot of seed oils.

          • I tend to agree – olive oil is one of the least offensive plant oils. Coconut oil, on the other hand, seems uniquely beneficial.

      • Jack Kruse

        Lipoprotein changes are all thermodynamic problems of plasma, proteins, lipids, water, and the hydrophilic or hydrophobic insides of the circulatory system but the key is to realize it all begins with a cell membrane meeting an environmental EMF that is must decipher. That is the basis of the cell signaling and circadian signaling. DHA is the only lipid capable of taking sunlight and making it an electric signal. Its ability is a quantum one.

        What distinguishes polyunsaturated fatty acids (PUFAs) from less unsaturated fatty acids is the presence of a repeating =CH-CH(2)-CH= unit that produces an extremely flexible structure rapidly isomerizing through conformational states. Docosahexaenoic acid (DHA) with 6 double bonds is the key example. DHA has the profound impact on all cell membranes in what it does to the lipid rafts. DHA is symmetry breaking for the lipid raft. Sound familiar to water’s ability? Just consider the “high disorder” DHA brings upon its interaction with cholesterol when the PUFA is incorporated into cell membrane phospholipids. Phospholipids demonstrate an aversion of DHA for the sterol that drives the lateral segregation of DHA-containing phospholipids into liquid disordered (l(d)) domains that are depleted in cholesterol. So DHA looks for cholesterol depletion to fill the gaps………with some key glycolipids like Phosphatidylcholine (PC) or Phosphatidylethanolamine (PE)

        These domains are compositionally and organizationally the antithesis of the commonly found lipid rafts in cell membranes. The much-studied liquid ordered (l(o)) domain that is enriched in predominantly saturated sphingolipids and cholesterol.

        One of the most important biochemical changes regarding aging is a change in membrane phospholipid composition. Phosphatidylcholine (PC), is the predominate head group phospholipid in the outer leaflet of the membrane. It is composed of two phospholipid groups opposing each other. PC also tends to incorporate a predominance of HUFAs, especially arachidonic acid (AA) on the Sn2 position, thus the outer leaflet is composed of a grouping of higher energy lipids than the inner leaflet. This varies with the curvature demands of the membrane since the tighter the curve would necessitate the preference for a smaller head group i.e. PC over PE, since PC has a larger dimension.
        In mammalian plasma membranes, the main variation occurs in the relative composition of phosphatidylcholine (PC), and both sphingomyelin (SM) and cholesterol. PC decreases with age while SM and cholesterol increase with age (Barenholz and Schacter 1983). DHA and PC are linked to functioning in the young brain. As the redox drops decade by decade the brain structure, physiology and optics all change. The big point is that in neuro-degeneration cholesterol is missing from the aging brain. This means when you have high cholesterol you usually are low DHA in CM.

        The impact of these shift in the outer membrane is difficult to envision for some. But a lack of DHA in cell membranes leaves us clue and symptom. If you lack DHA you will find comfort in cannabinoids both the endo and exo types when your LDL is high. This is why when people “go paleo” the LDL rises……when you go Epi paleo the LDL lowers and HDL rises naturally.

        The changes in the relative amounts of PC and SM are especially great in tissues, which have a low phospholipid turnover. For example, plasma membranes associated with the aorta and arterial wall show a 6-fold decrease in PC/SM ratio with aging. SM also increases in several diseases, including atherosclerosis. This is why PAD and bad brains seem to walk hand in hand. The SM content can be as high as 70-80% of the total phospholipids in advanced aortic lesion (Barenholz 1982, 1984). Both sphingomyelin (SM) and cholesterol are structurally similar to saturated fats. Cholesterol can change its conformation and action when it is loaded with electrons, but it needs DHA to get those electrons! This is why it is polar. Saturated fats have no intrinsic binding sites for electrons and this is why they are rigid.

        These changes involve every cell of the body. Every sensory neuron, touch, smell, taste, sight, hearing; skin, blood cells, brain neurons, endothelium, alveoli, immune cells, bone cells, etc. It involves the organelles within the cell such as the mitochondria the peroxisomes and the nuclear membrane. The concept of aging and DHA and PC decline is a dramatic shift in the body’s homeostatic ability.

        DHA, it turns out, has to be bound to the Sn-2 position on the glycerol back bone to get into the brain.

        The introduction of DHA-rich domains into the plasma membrane where they coexist with lipid rafts is the origin, in part, of the astonishing diversity of health benefits that accrue from dietary consumption of DHA. According to my OSF 3 blog, changes in the conformation of signaling proteins when they move between these disparate domains have the potential to modulate cell function.

        From a wide variety of biophysical studies, primarily done on model lipid monolayers and bilayers, suggesting that DHA may alter plasma membrane lipid raft structure and hence essential cell signaling events. In other words, it builds complexity of signaling. Complexity is built by electrons because they have the best thermodynamic properties. Energy without a lot of mass. This is why electrons and DHA is found anywhere signaling is critical. This fundamental role for DHA affecting a feature common to all cells, membrane structure and function, explains its wide variety of reputed health benefits in all tissue types.

        • rs711

          Hi Dr.Kruse,

          PMID: 15958274 “Cannabinoids & ceramide: two lipids acting hand-by-hand”. Reading this paper I was clued in as to the capacity of endocannabinoids to modulate membrane properties.

          Could you please explain how the mechanism described in this paper can be used to better understand the unmatched seizure control provided by CBD oil in intractable epilepsy?
          And maybe as well as to how this might be of interest to whole-body cellular metabolism?

          Thanks.

          PS: The ‘political correctness’ in the popular “Paleo movement” that has ignored the class of medicines that are cannabinoids is disgraceful for a self-purported modern health movement.

          • Jack Kruse

            I have a blog coming on this. The easy answer is CBD’s act as spackle on the CM when DHA is absent to help electron flow. It is tied to Ling’s work on electronic induction. ATP withdraws electrons while endo and exo-cabbinoids donate theirs to the CM structure to help it maintain its delta psi.

    • Jack Kruse

      http://www.ncbi.nlm.nih.gov/pubmed/20801459 Many environmental forces are now acting in concert to usurp energy from the highest energy systems so they decline in function first. This is how I see cognitive de-evolution occurring today. It also explains why we see metabolism affected early on, too. We are experiencing a torrent of Metabolic Syndrome today, because this is another way energy is brought into the system. If one eats low-energy dense foods consistently over time, like carbs and proteins, the result will be all the diseases tied to this syndrome. This parallels why elephants get larger eating grasses and vegetation using Kleiber’s law or the quarter power scaling law. This is why carbohydrates are linked to metabolic syndrome. They give mitochondria 36 ATP, while the beta oxidation of fats give it 147 ATP. This is why lipids and lipoproteins are altered in the manner they are by observation and experiment. Lipoproteins trend toward higher triglyceride levels as energy is lost while HDL is lowered. They are all tied to a loss of energy at the mitochondrial level. The proof I might be right is found in the observations we are now seeing at alarming rates in clinical medicine today. The problem for medicine is they do not understand why it is happening because they do not understand physics or compliant design changes due to thermodynamics at the mitochondrial level.

      • I spent yesterday reading studies from 25+ years ago and in one where they were comparing ATP yield and waste etc from various fuel precursors (sod it I can’t remember which study, brain stuff I think), the guy writing it made some flippant observation about how trying to use low yield fuel (glucose) which requires comparitavely ridiculous amounts of oxygen to power the cells probably isn’t an ideal strategy unless you dislike your mitochondria.

        Basically off-handedly predicted the coming prevalence of attention deficit disorder and Alzheimers etc.

        • Jack Kruse

          Well Ash I am glad to hear that…….I just posted a slew of data for Ivor above…….showing you why what you read happens……..its time people realize the Epi paleo Rx and circadian biology are the pathway for humans to follow. When we move away from it the shit hits the fan in many ways that tie back to these two issues.

          • This ? “its time people realize the Epi paleo Rx and circadian biology are the pathway for humans to follow.”

  • George

    Excellent post Bill – just what is needed at this point in history.
    The oxLDL hypothesis is supported by the epidemiological differential between nut and oil sources of linoleic (and alpha-linoleic) acids, in fact all the various hypotheses you mention are supported in various ways.
    I wonder how diet-heart hypotheses compare with mechanisms for non-diet causes of atherosclerosis, such as particulate air pollution and stress-induced elevations in leucocytes?
    Ghee prevents fatty streak formation in hypercholesterolemic diet-fed rabbits:
    http://www.ncbi.nlm.nih.gov/pubmed/23358722

    • Thanks, George.
      Mechanistically, there are so many possibilities, and it seems so difficult to even conceive of a way to test them directly. Air pollution, smoking, and stress could contribute to oxLDL, or indirectly to sdLDL via insulin resistance… or it could be that some form of inflammation is required (eg, the leucocyte mechanism you mentioned).

      or maybe the particles are just bystanders! Much of the reduction in CIMT is due to proliferation of smooth muscle cells… what’s their role in this?

      • …and to throw a cat amongst the pigeons, there are a few hypotheses being put forward that infectious agents are a causal driver too, being bound by LDL, which thus ends up trapped, immobile and engulfed by the arterial wall macrophage …..what a fun puzzle. Of course propensity to infection won’t be helped by an unhealthy high-carb impacted physiology, so some juicy interactions there too……!

        • The lipid hypothesis is dead. Long live the *new* lipid hypothesis!

          sdLDL, oxLDL, InfectiousAgentLDL…

        • Did you mean “high-sugar”? ‘Cos high-carb isn’t unhealthy if the carbs are from rice or sweet potatoes. Blue Zone populations, anyone?

          • George

            Exact words were “unhealthy high carb”.
            Rice doesn’t seem so healthy once bulk vegetable oils enter the picture, it’s not protecting the Chinese right now.

          • Rice isn’t to blame – bulk vegetable oils are the problem. Blue Zone populations are eating boiled rice sans bulk vegetable oils.

          • It seems like the only part of the shield that carbophiles have left is epidemiology.

          • Shield? Are you ‘aving a laugh? When mum was still alive, I used to chat to the Filipino carers in the nursing home about diet & nutrition. They said that they ate boiled rice in their home country (along with produce) and were slim. When they came to England, they ate a lot of bread & chips (that’s fries, to Americans) and got fatter. Quel surprise!

            There’s nothing wrong with boiled rice (or baked sweet potatoes), provided it/they hasn’t/haven’t been buggered-about with by being fried in a shed-load of oil.

            Y u so carbophobic?

          • No, my BS detectors go to max when people assert something is good because such-and-such eats/does it. Usain Bolt is the fastest man on Earth cos he eats a shitload of McNuggets.

            In the end I don’t give a crap about carbs, I just find the constant assertions of good/bad based on vague correlations to be a ‘tard sheild (defence).

          • My BS detectors are stuck on max, due to the constant BS I keep reading around the blogosphere about how bad carbs are, when it’s actually sugar and/or grain dust that’s being referred to. See http://nigeepoo.blogspot.co.uk/2014/06/the-conflation-game.html

          • Tried to delete comment above to avoid any further stupidity, no worky.

            Anyhoo I’m not interested in the macronutrient fight, I don’t even believe in “macronutrients” as they stand, it’s right up there with setting calories in stone as the dumbest thing we as a species ever did for our lifestyles and health was to delineate food down to 3 major categories.

            This only ends in giant piles of ideology and pure dumbness.

          • “This only ends in giant piles of ideology and pure dumbness.”
            I agree.

        • Jack Kruse

          infections cause inflammation which lowers the EZ of water around the MINOS of cytochromes in mitochondria. Infections have lower pH and this blocks the flow of protons at ATP synthetase. The proton channel in ATP synthetase is made by 4 hydrophilic proteins. Infections change their function by making them more hydrophobic and lowering proton flows out of mitochondria. This reduces ATP function, lowers O2 reduction, and radically is reflected in water chemistry around mitochondria. This results in massive changes in NAD+ at cytochrome 1. It also radically changes RNS and ROS within the tissues Ivor. This causes a redox shift in mitochondria to a Warburg metabolism. This is why CVD, obesity, and cancer have all been linked to infectious disease. The common denominator is altered mitochondrial function. When this occurs it favors karyotype constriction when the voltage change is massive. All tied to electron and proton flux in mitochondria. It all makes sense when you see how mitochondria really work. http://www.bioinitiative.org/report/wp-content/uploads/pdfs/sec16_2012_Plausible_Genetic_Metabolic_Mechanisms.pdf

          • Jack Kruse

            Hypoxia has major effects on mitochondrial efficiency and biogenesis in CVD, obesity, and cancer. What separates them all is intesity and rapidity of occurance at the mitochondrial level. Mitochondrial signaling is a big deal in the case of cancer because superoxide generation from cytochrome one (NAD+) is altered forever. In CVD and obesity we can alter it by using autophagy as the change program to fuel mitophagy. In cancer, this is lost. These people must use other means of energy generation in mitochondria. When nuclear NAD+ levels are low, HIF-1? is stabilized chemically and is not degraded by von Hippel–Lindau protein (pVHL). Bill talked about this briefly in his last blog. In non cancerous states like CVD and obesity, VHL degrades HIF-1? very rapidly. The time course is directly correlated to the plasma redox potential in the obese and those with heart disease. This is why there is a correlation effect in liporproteins. The thermodynamic changes are constantly altering shape and conformation based upon the plasma redox. Why is this point a big deal in cancer? pVHL ties directly to the ubiquination pathways in cells. Ubiquination tags cellular proteins, glycoproteins, and cell membrane lipids for replacement. They must be working well on a atomic or quantum level to signal environmental cues from the environment to the mitochondria. They are all yoked to circadian biology by SIRT 1. Bill last blog points you to this linkage. This can not be maintained in cancer. I have also told many on my site that ubiquination or cellular catabolism and resultant anabolic processes are the most costly things a cell can do on an energy basis. In cancer, energy is already low because you can not make ATP well because cytochrome 1, 3, and 4 proteins are not being expressed by mitochondrial DNA.

            When all these things happen in simultanity within a cell, as occurs in our modern world, cells are “metabolically shifted and reprogrammed” to use aerobic glycolysis in the presence of normal oxygen. This is how a Warburg metabolism occurs. HIF-1? inhibits a chain of events that ultimately results in a reduced expression of the mitochondrial transcription factor, TFAM, which normally migrates from the cell nucleus to the mitochondria to stimulate mitochondrial DNA replication. This is 100% an epigenetic shift to the environment the cells are in and not from the DNA they inherited from their parents. This is why cancer researchers remain without a cure. Cancer is an epigenetic disease not a genetic one. When you have hypoxia or low ATP it causes massive changes to proton flows at the ATPase which cause karyotype constriction. Metformin reverses this. This is why it has been helpful in the obese, those with T2D and CVD.

            As a result of this epigenetic shift, mitochondrial encoded genes are altered and their expressed function changes. These changes can pass on this environmental information to future generations via our germ cell lines by leptin. Leptin controls oocytes selection and fecundity in humans. It is 100% tied to the delta psi or electron density of plasma that bathes the ovary. It mimics the effect we see in vessels and coronary vessels in CVD. This is why today we are seeing massive neolithic disease generation in younger people today. Since 1970, these children are being born with lowered redox potentials because of the environments their parents were forced to exist in by societies choices.

            When HIF-1? inhibits mitochondrial transcription factor A this can’t occur. Mitochondrial transcription factor A is abbreviated as TFAM or mtTFAM. This is a “big assed” deal in cancer. These circumstances allow nuclear encoded mitochondrial proteins to still to be created via the transcription factor Nrf1. But where the rubber meets the road in cancer is with TFAM. When TFAM is suppressed by HIF-1?, Nitric Oxide mitochondrial-encoded protein components of the electron transport chain are expressed even though their mitochondrial DNA mutations do not allow them to properly tunnel electrons from foods. This RNS amplification also is what opens the endothelium to an oxidized plasma. This changes the polar nature of cholesterol. This oxidizes it. It is also what oxidizes lipoproteins to induces the sizes and particle sizes of the lipoproteins. When these altered cytochrome proteins are placed into the ECT they become non functional in passing electrons to oxygen. This lowers delta psi and decrease ATPase function. AMPK is raised. This means no oxygen is reduced. This results in mitochondria that can no longer make ATP at all; because they still have a defective ECT that has to “run in reverse” to get around this situation. Think Hyperlipid protons series now. The significance of this is, that unfettered “reverse electron transport” results in the production of uncontrolled amounts of charged free radicals from the mitochondria. These are both ROS and RNS moieties I have been telling you about.This is how CVD comes about. It is common in obesity, cancer, and atherosclerosis and aging and it is why all disease correlate with one another. It is quantum changes at cytochromes that cause it.

          • Jack Kruse

            Mitochondria normally pump out huge amounts of positively charged protons. In fact, this action is what drives the earth magnetic field and it is what drives your life force. Water is the key missing point in these discussions. (http://www.slate.com/articles/health_and_science/science/2014/03/water_in_earth_s_mantle_revealed_by_diamond_containing_the_mineral_ringwoodite.html?wpisrc=burger_bar). When water is missing it alters the charge in a cell membrane. Cell membrane charge is directly tied to its omega 3 content. this brings us full circle in this thread with respect to joshua comments. This altered electrical charge on the inner mitochondrial membrane immediately destroys the pH gradient of the proton motive force in mitochondria. This directly destroys proper redox signaling in mitochondria. The charge on the inner mitochondrial membrane drops quickly. This then creates the “primordial molecular signal of aging and disease” we see in all experiments. The signal is mitochondrial dysfunction with a higher free radical production. All of these events can be traced back to inadequate NAD+ in the nucleus not the cytoplasm. Without adequate NAD+ in the nucleus, SIRT 1 and SIRT6 cannot function. Sirtuin 1 and Sirtuin 6 is directly tied to excessive nuclear aging. Why is this a big deal?

            SIRT 1 plays the pivotal role as a “deacetylase silent mating-type information regulation 2 homolog”. What does this mean in english? SIRT1 is the major molecular effector of the environment in shaping the circadian epigenetic landscape present within the quantum cell. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, SIRT 1 links epigenetic regulation to the circadian clocks in our brain and in tissues to help control and master the direction of the plasticity of the response to the environment. (Think metastability) This allows a cell to read and react to envionmental triggers normally. In diseases we lose this ability.

            In the nucleus is where our somatic DNA resides. This is the DNA that the oncologist and their researchers have been wasting billions of dollars studying. The problem is upstream of somatic DNA. It is an epigenetic mitochondrial shift that causes cancer. This is where the epigenetic changes from altered mitochondria hijack our DNA mechanisms in the nucleus and cause all the changes oncologists are studying. None of these changes are the initial cause. This is why cancer remains vexing to them. The key change is NAD+ levels in the nucleus. Guess what replenishes NAD+ fastest? A ketogenic diet does. It works best when it is a ketogenic diet that has a lot of seafood in it. We need the DHA to protect and maximize the charges on membranes. You might begin to see why I wrote my book called the Epi-paleo Rx now. It is the cheapest easiest way to avoid all neolithic diseases like CVD.

          • Jack Kruse

            It turns out that nuclear NAD+ is a mandatory co-factor for all of the proper functioning of sirtuin signaling in humans. Sirtuins control the mTOR (SIRTUIN) pathway in humans. Many doctors talk about the mTOR pathways but few of them truly understand how it answers to the redox pathways in cells. What happens in a worm or yeast is not congruent to humans. This is why CRON data in primates has not yielded the same results as Cynthia Kenyons worms. Worms and yeast use SIRT 2, 3, 4, 5 and we humans do not. We use SIRT 1 and 6. Researchers across the world are slowlywaking up that quantum tunneling of electrons is directly linked deficiency of NAD+. I am hoping I wake up the ancestral community to this fundamental fact in the nucleus of cells. This produces a state of “pseudohypoxia”, where there is adequate oxygen levels but also high levels of HIF-1?. 24/7 carbohydrate exposure cause this effect. This is why guys like Nigel I chuckle at. They just have no clue what they do not know. The number and quality of mitochondria are directly proportional to the effects of electromagnetic force brought to bear on the mitochondrial cytochromes. Seasons alter that force on the cytochromes. 24/7 carbohydrates deliver fewer electrons with higher energies simulating a summer energy footprint to cytochrome one. This generates excessive ROS and RNS and the epigenetic changes in mitochondrial DNA begin.

            Carbohydrate foods are designed to grow and be eaten only in long light cycles and seasons and they enter at cytochromes and give us a specific “redox footprint” to the mitochondrial cytochromes. Delta psi is also known as the inner mitochondrial membrane electric potential. We can also call it the redox potential of the cell membrane. Saturated fats (FFA’s) drive reverse electron flow through complex I when delta psi is high (redox high) by adding electrons directly to the CoQ pool via FADH2 at cytochrome 2. When delta psi is lower (low redox potential) or depressed (think too much glucose), oxygen consumption is also depressed, and NADH accumulates at the expense of NAD+ levels, which drop. This is why saturated fats help CVD. It is obvious if you get how mitochondria function. A reduced CoQ couple is required for reverse electron flow through cytochrome one. Therefore you can see excessive glucose blocks reverse electron flow and can shut down energy production and superoxide production. The brain and heart hate superoxide but they loves ketone production. http://www.nature.com/nature/journal/v487/n7408/full/nature11314.html You might want to click on that hyperlink you just passed. I hope you get why seafood and circadian biology are big in this discussion. It is critical to understand. Few do.

          • Jack Kruse

            When you consider CVD you must understand plasma redox to understand lipoprotein function. Few do. If you do not think electrons have a direct quantum effect consider this link:http://www.ncbi.nlm.nih.gov/pubmed/11687303 Red blood cells are glycolysis-dependent cells which lack mitochondria naturally. NADH is recycled out towards the plasma membrane transport system. RBC’s naturally export 2 electrons to give rise to intercellular ROS which acts a signaling mechanism. This oxidizes ascorbic acid (vitamin C) and directly affect glutathione levels inside the cell as well as raised iron levels. Ascorbic acid is an antioxidant that maintains hemoglobin in a reduced state and minimizes RBC oxidative injury. It directly effects collagen and fibrin actions in RBC’s. When electrons are missing the RBC’s are oxidized RBCs are elongated and not biconcave and easily deformable. The oxidized ascorbate (AA) then transitions to its deoxy form called dehydroascorbic acid (DHA). When DHA enters the erythrocyte its reduction to AA regenerates another NAD+ and this is able to reduce glutathione to make the RBC a deformable biconcave cell. RBC’s normally exhibit a Warburg metabolism their entire life because they have no mitochondria because their cell is loaded with hemoglobin. Two electrons cause this effect!!! http://www.cardiab.com/content/12/1/25

          • Jack Kruse

            The Sinclair paper linked above shows that mitochondrial dysfunction and this Warburg-type metabolism are fully reversible with the supplementation of NAD+ precursors (niacin) or a DHA laden ketogenic diet. Ketosis also happens to replenish NAD+ for the nucleus! Ketosis is protective because it allows passage of electrons and protons from fats (FFA) to make some ATP and salvage the bad mitochondria they possess and keep them from oncogenesis. Ketogenic diets have also been shown to aid deep sea divers and special force soldiers overcome situation where they face chronic hypoxia. Ketogenic diets help prevent brain cancer and heart disease and they treat it best. Read this hyper link. http://www.nature.com/nature/journal/v487/n7408/full/487435a.html There are many reports that a sick brain does not really use glucose (you’d never know that reading the blogosphere Kresser or Jaminet) but changes it to lactate which neurons love to use as a fuel with fats. Here is where saturated fats have a protective role. The humans brain does like fats and lactate together, but guess what also likes this combo of lactate and fats? All other tissues in your body do. So does your heart!!! So when you eat fat you will not get CVD, cancer, or get fat. (Big wisdom point here) Lactate usage by the brain and heart appears to be the best way of postponing apoptosis (cell suicide), short of abandoning your brain/heart mitochondria altogether. This is why CVD walks hand and hand with neurodegenerative disorders because both tissues have high mitochondrial dependency. Glucose use comes in as a second choice in the heart and brain. GIK is hogwash for CVD. But the K+ is the key. K+ links water molecules to ATP molecules stochastically. This is what Gilbert Ling proved 60 years ago and no one seems to know about it. Potassium levels tell you about the relationships to ATP. For every 0.3 mEq below 3.8 mEq that potassium is on a standard blood lab draw, means there is 100 mEq deficit inside a cell. The atomic size and its redox potential is huge for potassium “gluing of water” for it to function as the optimal electrical adapter to transfer energy throughout the cell coherently. ATP is designed to unfold proteins fully to open their carbonyl and imino side chain groups on all amino acids to intracellular water. This action allows binding and polarization to separate water into subatomic particles that are positively and negatively charged. This action is called building or expanding the exclusion zone (EZ) of water.

          • Jack Kruse

            Each molecule of ATP in a cell controls 8,800 water molecule binding sites and 20 potassium ions to allow water to become structured inside every cell of your body. The first step in photosynthesis and ox/phos is the charge separation of water.

          • Jack Kruse

            Gary Taubes quoted Hans Krebs in Good Calories Bad Calories by saying, ‘All three major constituents of food supply carbon atoms’. Most biochemists, clinicians, and scientists believe that metabolism is all about the carbon cycle. I think most of you realize by now that I do not agree with this. It is all about electrons. This is why input to the mitochondrion is called ETC. The second reason is that Gilbert Ling’s work showed us it is not about the amount of ATP made or about carbon recycling, but about the charges added or subtracted to the backbone of the proteins. Ling showed us 60 years ago that electrons and electrostatic charges change the superstructure around carbon atoms. The superstructure is what we call proteins. These charges can elastically deform and compliantly redesign carbon back bones to lead to innovative changes. this is how lipoproteins alter their shape, size and density in CVD.

          • Jack Kruse

            The inner mitochondrial membrane is where the action of life happens. It is covered by some unusual proteins. Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Here you can see how proteins undergo elastic changes as electrons are added and subtracted to its structure. When electrons are abundant, the mitofilin works to maintain ETC. When it is not, the result is autophagy or apoptosis. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed as the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane where ETC occurs. The inner boundary region is closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans. Alterations of MINOS subunits are associated with multiple pathological conditions.

            Humans are designed to eat an electron dense diet because they have a shortened gut and an expanded brain that steepens their energy needs while restricting their sleep needs to 7.5- 8.5 hours. All of these features are tied to how well we can access autophagy. This implies that humans must have evolved around an environment providing a constant source of electron density from their environment. Humans who eat like Gazelle’s do, or lose electrons to their environment faster than they collect them, are now known as people with diabetics,fibromyalgia, MS, sleep apnea, and chronic pain and heart disease.

          • Jack Kruse

            It turns out that how water interacts with MINOS is hugely important and not well known. Water is an energy converter, or a liquid nano-machine that takes all radiant energy and changes it to other forms of energy that a mitochondria can use and distribute over a cell. Water surrounds MINOS wherever it is found in us. Photosynthesis and oxidative phosphorylation in mitochondrion have some major things in common. Water is one of them. To you detriment, modern science still fails to realize the importance of water in photosynthesis and in mitochondria. Plants are capable of taking sunlight and using non living pigments and chemicals to make simple chemical compounds and elements needed to power life. Here we have an example of how “an EMF” brings life to life. Mitochondrion use the Vitamin A and D cycle in your brain to do the same thing using light.

            EZ charge separation is the generic first step of both pathways. In fact, the goal of both energy generation pathways is to split water. In photosynthesis, this happens due to light absorbing chromophores that lie adjacent to water. To synthesize one molecule of glucose by photosynthesis, 24 electrons must be removed from water molecules. These electrons are held by the redox potential of oxygen (+0.82V). They are pumped uphill to carbon atoms that are partially reduced to a carbohydrate with a redox potential of -0.42V. The potential energy difference is 1.24 Volts. This change in free energy is in the positive direction. The result of this energy transfer creates 2870.2 kJoules of energy. This is an astounding amount of energy capture when you understand the quantum dance of the sun on water.

          • Jack Kruse

            In mitochondria energy from the exothermic reaction of water forming from O2 and the enzymatic burning of foods to fuel to electrons that funnel into ETC. This results in infrared energy in heat and ATP production. infra red heat is the energy from the sun that water absorbs best to induce charge separation in water to generate massive exclusion zones in water. When one mole of H2O is created from one H2 and half O2, 286 kJ of power are released. In mitochondria this all happens from one mole of water. That power is astounding. Mitochondria make life work by solar power, just like plants do.
            Humans are designed to catch electrons in their central nervous system using DHA in their cell membranes. They also have higher levels of DHA in all their tissues compared to other mammals for the same reason. Humans then deliver electrons and their energies, information, and spin through the DC current in the interfascial water below myelin and outside the axon to all parts of the body. (Robert O. Becker alert) Eventually these electrons wind up in the mitochondria ECT. This is a critical point between the two major arms of metabolism. Mitochondrial cytochrome proteins are like small optical magnetic nanomachines for electrons and protons. They are designed to tell the difference in the energies, information, and spin of electrons and protons. Higher energy photons from the sun in summer go to cytochrome 1. Here water is turned into an EZ to power life from water. Lower powered photons of fall and winter go to cytochrome two. The cytochrome proteins actually have the ability to decipher the season based upon the characteristics of the electrons delivered to it. Circadian locomotor output cycles kaput (CLOCK) is a nuclear transcription factor that is a component of the central autoregulatory feedback loop that governs the generation of biological rhythms. This is how the cell membrane senses the seasonal electromagnetic changes. Electrons are sorted by our mitochondria to harvest their energy, information, and spin characteristics for our body and brain to use, setting our metabolism to meet environmental demands. This is why data now shows that when circadian cycles are off, exercise loses its benefit. Bill had a post on this too. Autophagy decreases when circadian biology is off. If you look at the work of Ernst Van Schwarz from UCLA (cardiologist) he shows in his work that heart failure occurs due to a failure of autophagy and its harbinger is cardiac fibrosis and cellular senescence at a microscopic level.

          • Jack – I can only say that I am in awe. I will not pretend that I have the knowledge to properly follow your mechanistic summary, but in the coming weeks I will try. I am applying engineering problem-solving experience and techniques to this challenge, which includes technical breadth as appropriate and depth where there may reside data that conflicts with the thrust of root cause hypothesis. As you know, a given hypothesis can have many levels, from the articulation of the important high-level variables (thus allowing actionable solution for the issue), through to the exact explanation of every nuance residing in the fundamental physics of the problem (ideal, but which I am sadly unlikely to achieve ). In short, pending further study, I can only rely on my intuition and instinct around your detailed explanations above – and this tells me that you are light years ahead of the existing “masters of the universe” researchers, who wallow in undeserved self-aggrandisation and loathsome hubris. Have you communicated with Peter Dobromylskyj at http://high-fat-nutrition.blogspot.ie/ – I’m at a loss to think of someone else who could intellectually spar with you in this arena! Thank you – Ivor

          • LOL seen the latest rally?

            –> http://high-fat-nutrition.blogspot.com.au/2014/06/there-are-researchers-within-worlds-of.html

            I have no training in… ANY, discipline, but grew up teaching myself programming and ancient languages, advanced heuristics, and dabbled in astrophysics and “quantum” mechanics.

            But yeah, since turning my attention to biology/biochemistry I’m still plodding along getting my head around how deep to go, I mean how low on the subatomic scale do you need to comprehend to figger out how to live?

          • Considering I still don’t have the answer to a seemingly simple question I came to this field 5+ years ago for:

            Why eat plants? Why does everyone believe it’s healthier than just eating meat, and indeed believe it’s actually necessary at all?

            Apart from “cos some are delicious” I’m yet to hear a plausible theory.

            Epidemiology doesn’t count.

          • Hahaha, ok Ash, you’ve been asking this question for a while. I’ll write a blog post for you 🙂

          • Heh, good luck! 😀

            Mark Sisson tried his hand at it, and failed miserably:

            –> http://highsteaks.com/do-you-need-veggies-to-be-healthy-a-response-to-marks-daily-apple-caveat-vegor/

            Not a single person has ever demonstrated plausible reasons for consuming plants beyond medicinal, caveat supplementation, epidemiology, anthropology, and taste/enjoyment.

            Those are all *ok* reasons or justifications, but none are compelling enough to make the ASSERTION that you NEED to, which is where I have the problem. If someone asserts, they need to demonstrate, I take nothing on faith. Except Faith from Buffy, Dushku is freakin’ hawt.

          • Oh an Amber (Ketotic) tackles it more succinctly and less meanderingly than I do:

            –> http://www.empiri.ca/2014/02/response-to-mark-sissons-assertion-that.html

          • ugh. DONE.
            …i feel dirty

          • Haha well done! 😀

            From a quick scan it still all seems to fit into the aforementioned “lifestyle” categories for plant consumption:

            “medicinal, caveat supplementation, epidemiology, anthropology, and taste/enjoyment”

            I’ll take a deeper more objective look later. Until then, I stand by this:

            https://twitter.com/AshSimmonds/status/444262724269142016

          • Jack Kruse

            Put nature’s laws in your medicine cabinet……..every Ash is quantized. Realize it an adapt.

          • Ash, this is only my opinion, but I think it’s important to try to understand the mechanisms as thoroughly as possible so I don’t misinterpret cause-effect relationships that appear the literature, various n=1 testimonials, and even my own experience.

          • Oh I’m with you, what I’m talking about though is what level do you stop – how deep can/should you go?

            I’m at the point now where this is all completely internalised, I don’t even have to *think* about food any more, I instinctively know to select the best sourced fattiest meat/seafood/eggs, and limit other stuff to taste/enjoyment.

            You can plainly see how blissfully ignorant of the whole topic I was just 5 years ago, here’s the genesis of my journey:

            –> http://aussieexotics.com/forum/off-topic/meat-is-bad-good-for-you-3472.0.html

            Basically, people see me wolfing down fatty steaks covered in butter, and as previously said elsewhere: I finally got sick of people thumbing their noses at me over the table when they ordered a salad with extra bland or a skinless chicken breast covered in white water flavoured sauce for their health and telling me I’m killing myself when I got my usual steak covered in butter or pork belly in oil etc, and barely touched the veggies unless they were chips.

            All that stuff about fat and red meat and cholesterol etc I just flat out ignored, because I grew up feeling amazing eating especially fatty meat, but really I just didn’t care what the authorities said. However I was approaching mid-30’s so mortality and health in later life starts to weigh on the mind a bit more, plus I was fairly overweight (beer, chips, bread, pasta, noodles were also with every meal) but otherwise fit and healthy, so I wanted to know for sure.

            Thus I set out to find everything I could that proved meat and fat were bad for me so it would be the final impetus for me to finally embrace the healthy low fat lifestyle that I just ignored my whole life, and open a new chapter of health to the end even if I had to just suck it up and have my meat fixes in small occasional portions for the next 30-200 years.

            Well, we know how that research ended up… :p

            It didn’t take long before I discovered the truthiness of sat fat and cholesterol and all the other lipidology. I’d since grown bored of the topic until just recently with Ivor’s presentation, which as I said to him at the time the science part is the most coherent explanation of how it all works from end-to-end, and stitches up the concept in ~half an hour which in reality took me probably several hundred hours of study to really understand.

            Anyhoo, morning rambles aside, I do keep my eyes on the cutting edge of research, and even listen to Jack occasionally!

            https://twitter.com/AshSimmonds/status/409089779121152000

          • Jack Kruse

            Don’t be in awe Ivor…….we are all in this together…….I just am a bit more curious than most and I dig a lot deeper than most to find fundamental reason by nature’s laws shit happens. It is why I wear a target on my back. I hope this helps you in some way. Bill blog has helped a lot people see that maybe some of the things I post are beginning to have a strong physical basis when you understand the details

          • the quality of animal & human studies in circadian biology has been improving at an exponentially increasing rate in recent years. The science backing many of Jack’s recommendations is becoming, quite clearly, true. This cannot be denied.

          • Oligodendroglia metabolically support axons and contribute to neurodegeneration
            full text: http://bit.ly/1iPIxXH

  • rs711

    The idea of the apoB mechanism being the proximate and primary trigger of CVD via forced endothelial entry seems a little too dismissive of its a alternative roles in the body; immune regulation (LPS binding), cell maintenance (fat transport) & so on. Something so vital ends up doing damage because of the ‘circumstances’ it’s in, not because it suddenly turns bad. The perturbed switch in the metabolic cellular ‘milieu’ of vascular tissue is my guess as to why things find themselves where they shouldn’t.

    The more plausible scenario is that people (lipoproteins) will come inside if the door is open (endothelial penetration), not that they’ll try to open a well-locked door they’ve otherwise mostly ignored.

    • *like*

      • Joshua

        This is interesting: http://www.mdpi.com/1660-3397/11/11/4435/pdf

        There is an effect of LC n-3 PUFA and Actin Cytoskeletal Rearrangement. I wonder how compromised tissue function is due to disproportionate n6:n3 ratio. If n3 can have an effect on actin causing structural changes then it likely could have an effect on tight junctions. ….and Zonulin with increased permeability of Gliadin

        Leaky gut due to a high amount of n6? Could all of our modern chronic health problems due to Crisco, Canola, Chicken and Tofu????

        • George

          I’ve read somewhere that some types of oxLDL are anti-atherogenic (but I can’t find the list of those types now). If these were oxidised DHA types rather than oxidised LA this would be consistent with other roles of DHA peroxides.
          Particulate air pollution, traffic noise, and atherogenesis
          http://www.medscape.com/viewarticle/802965

        • these fatty acids likely have both direct and indirect effects on the intestine – 1st pass when they’re entering from the lumen (diet-derived) – and 2nd pass when they (or their metabolites) enter via the bloodstream.

          Lots of controversy about the n6:n3 ratio, ALA vs. EPA/DHA, absolute amounts of EPA/DHA, etc…
          Avoid processed vege oil & eat seafood. Done & done.

        • Jack Kruse

          anything that alters the size of the cytoskeleton to make it large causes it to be energy inefficient. This is fundamentally a thermodynamic issue tied to mass equivalence.

    • LDL particles can do a lot of things. Their true purpose, however, is unknown.

      • rs711

        It’s as if we’re trying to predict long-term weather patterns when we’re still unsure if the thunder causes the lightning or vice-versa

      • “Their true purpose, however, is unknown.”
        Their true purpose is to take over the world by stealth. 😉

        But seriously, I thought the true purpose of LDL particles was to transport cholesterol, cholesteryl esters and triglycerides around our bodies, in our blood.

        • rs711

          Those few things do many things – hence the difficulty in distinguishing cause from effect in their little lives.

    • George

      “Repairs gone wrong” – improperly constructed, not fully disassembled, cycle repeating as cell damage amplifies inflammatory signalling – is the pattern in most chronic degenerative diseases. This model is more complicated to apply to vascular disease because the system isn’t localised in the way say cirrhosis or arthritis are.

    • Joshua

      I agree and will expand.

      Dr. Dayspring points out in his video that the actual structure of the LDL particle can be altered by increasing the n6:n3 ratio. This has the effect of changing the confirmation site location slightly which can reduce uptake and leave elevated levels in the blood.

      A high ratio of n6:n3 (60:1) will likely alter all the cells in the body and change the structure of the phospoulipid bilayer in every cell. On a macro level this could alter the tissue function itself. Altered endothelial tissues may lead to increased endothelial penetration.

      These two points in combination (Increased LDL and altered tissue function) caused by n6:n3 imbalance could be likely causes of increased CVD. This is also likely why we see inverse association with increased n3 intake.

      • my only comment is that while this all sounds very reasonable, it is very difficult to prove experimentally…
        at the end of the day, we’re still left with a lipid hypothesis.

      • Hi Josh. I didn’t hear Dr. Dayspring say that the shape of LDL particles could be altered by changing the n6:n3 ratio, just that unsaturated fats and cis vs. trans conformations can play a role. This is at around minute 43:00.

        • joshua

          You’re correct. It was just cis vs trans.

          However, I inferred that changes in cis/trans mean n3/n6 + oxidation. Increased n6 is likely going to increase trans confirmation. And even a slight increase could shake the balance.

          PUFA-containing phospholipids impart unique structural effects on (bi)layers which can alter confirmation and Ca+ concentrations

          There are also studies showing that PUFAs high in n6 can interfere with formation of the immunological synapse. Which is a structural confirmation. One can infer that structural changes are occurring throughout all cells. We know that n6 also has an effect on tight junctions and cytoskeleton arrangements. Creating tissue malfunction.

          Our body is an engineering marvel. We are literally mixing the concrete wrong and the building is crumbling.

          http://ajcn.nutrition.org/content/84/6/1277.long

          http://www.ncbi.nlm.nih.gov/pubmed/9887028

          http://www.ncbi.nlm.nih.gov/pubmed/15703198

          • w6/w3 ratio being relevant has significant data behind it, but exact mechanism…..I like the Helsinki Businessman Study – main intervention was lower sat fat, and seemingly stuffing them with w6 in a vain attempt to validate the diet-heart BS, but the high machine-lubricant intervention group also had lowered alcohol and sugar too! Result was a little known debacle – this one got buried quietly needless to say, but I never had quite the appetite for w6 after perusing it……..!

          • pic this time

          • Jack Kruse

            OK Ivor………here is the most significant data I can give you: DHA is a natural ligand for RXR – obligatory step – stimulates > 107 genes that developed the brain 600 million yrs ago.
            Nutrients and many other environmental factors have also been found to influence epigenetic programing of our DNA either directly or indirectly via metabolic sensors. Peroxisomal proliferator-activated receptors (PPAR’s), the vitamin D receptors, and the retinoid X receptors (RXR), and the retinoic acid receptors (RAR) are all examples of the nuclear receptors that interact with the brain cell membranes to control inflammation and metabolism all over our bodies. It turns out that PPAR’s are the receptors that are at the crossroads of where inflammation and metabolism actually cross. These are specialized lipid sensors that pay attention to our balance of omega 6 and 3 levels.

            What we eat is really damn important when you have 3 lbs of lipid in your head called a brain. If you eat outside our design you get sick.

            Levee 13 in the Quilt talks in depth about the effects of certain lipids on PPAR. It turns out DHA/EPA have massive effects upon it. Moreover, it also turns out that fish based PUFA (DHA) is also a ligand of retinoid X receptors (RXR), and RAR binds most of the forms of Vitamin A in our bodies. Remember from the Hormone 101 blog to make hormones we need Vitamin A and T3 to be present in good concentrations to convert LDL cholesterol to pregnenolone. Pregnenolone then undergoes transformation to the rest of hormone chain in humans, provided cytokine levels are low. That hormone chain ends in Vitamin D production making it an ideal way to tell us what is going on in that engine.

            DHA, the fat in shellfish and seafood, has direct epigenetic affects on human epigenetics

            DHA turns solar light into electric signals……….it is where optogenetics began in evolution.

          • Jack Kruse

            The mind is the sum total function of the central nervous system (CNS) and its endocrine secretion is called a thought. That secretion can directly up regulate DNA and RNA activity with gene expression and protein formation. This means that a thought has a tangible action. This ability is found in the biochemistry of the DHA molecule itself.

            Few people realize the possibility is that DHA in vivo plays a more direct role in neuronal signaling, in which some special properties conferred on the membrane by DHA chains exert an influence on membrane electrical phenomena (Bloom et al. 1999) This implies that the DHA molecule itself has some special electrical abilities and can exert quantum effects in vivo. The 6 double bonds in DHA allow for its electron cloud in the molecular structure of DHA to become a very special fatty acid with respect to unique properties. Humans exploit those advantages more than any other mammal on this planet. It has been put forth that some polarization of ?-electron clouds might occur in the DHA structure, and perhaps even be transmitted from one double bond to another, either within a given chain, or between neighboring chains in the membrane. This means that DHA has different properties in the lipid structures of the brain than it does when a researcher studies it in the lab. It implies these effects are lost when fish oil is in a pill form outside of its evolutionary package of shellfish. This is why supplementation falls far short of eating fish.

          • Jack Kruse

            DHA has 6 allylic double bonds. This is more than any other PUFA. Deuterium selectively incorporated into the bis-allylic position inhibits lipid peroxidation.
            • An ROS molecule (e.g. a superoxide) may finds itself surrounded by a dense forest of PUFAs; it damages one of them, and a chain reaction follows until the chain hits on an antioxidant and stops.
            • Toxic carbonyl compounds (HNE, malonic dialdehyde, and many other) then can leave membrane and do much damage elsewhere.
            • PUFAs deuterated at the bis-allylic positions do not sustain the chain reaction, while being otherwise identical to natural PUFAs.

            DHA is critical to membrane function and you need seafood to get it, and get a lot of it because living life creates a lot of positive charges that try to destabilize our membranes.

          • Jack Kruse

            WHAT IS SPECIAL ABOUT DHA? Why 600 million yrs track record since the cambrian explosion?

            ===== CH3///(/////COOH DP n-6

            delta-19 double bond missing

            CH3/=/=/=/=/=/=/COOH DHA n-3

            CH3/=/=/=/=/=///COOH DPA n-3 delta-4 missing

            DPA n-3 THE delta-4 DOUBLE BOND IS OMITTED DPA n-6 THE delta -19 DOUBLE BOND IS MISSING (only one double bond difference!)

            Although the n-3 DPA is a precursor for DHA neither DPA replaced DHA in 600 million yrs of evolution, so these two double bonds may be critical to DHA’s role in signaling membranes.

            WHY?

            Docosahexaenoic acid: Alchemy optimized conformation:

            double bond 1,3, 6 planar and pi-pi orbitals co-planar.

            The planar-ness of the preferred DHA conformation is a fundamental characteristic of the six double bonds separated by CH2 groups. If there are only five, the corresponding molecule cannot be made planar.

          • Jack Kruse

            once again you see shades of my OSF 3 blog about now…….. huh? 3 D molecular specificity is key.

          • Jack Kruse

            n-3 DPA odd number of double bonds and 1, 5 planar

            < 8.4Angstroms……….

            This means only one thing……in solid state physics. Alternative positive-negative sets of the allylic double bonds set the stage for semi-conduction.

          • Jack Kruse

            Calculations based on the least occupied orbitals for DHA show that the bonds have + and – lobes and that the + and – signs of orbitals of the two different hydrogens on the CH2 groups also have + and – signs related to (typically opposite to) the signs of the adjacent p bonds.

            This is a simple mechanism to explain electron coherence over a large distance, even though the double bonds are not extended resonance structures across a sequence of carbons. None of this works with DPA which has one double bond missing leading to a saturated chain too long for tunnelling.

            Nuclear Overhauser Enhancement an NMR technique to detect the potential for electrical function demonstrates the feasibility of electron responses within DHA

          • Jack Kruse

            1-acetyl,2-docosahexaenoyl-glycerophosphocholine (AceDoPC) has been made to prevent docosahexaenoyl (DHA) to move to the sn-1 position as it rapidly does when present in 1- lyso,2-docosahexaenoyl-GPC (lysoPC-DHA), an efficient DHA transporter to the brain and all cell membranes. When incubated with human blood, AceDoPC behaves closer to lysoPC-DHA than PC-DHA in terms of binding to plasma albumin and lipoproteins, and DHA incorporation into platelets and red cells cell membranes. This requires a good plasma redox to happen. This is the same issue tied to the lipoprotein issues seen everywhere in medicine. If the plasma redox is off then CM physiology is off and DHA never gets to sn-2 position and never gets assimilated properly to CM. Why is this big?

          • Jack Kruse

            DHA controls the inflammatory process and epigenetic switches so they work well. when they are in sn-2 position. Electrons are directly tied to the amount of DHA in our immune cells. I get aggravated with all the talk about lyme, virus’s and all the viral biotoxin diseases………yet few get the link to DHA or the ratio of 06’s and 03’s in the all cells but really matter in immune cells. And in the pathways for resolution of inflammation.
            Fatty acids have germicidal effect for fungi, viral particles, and bacteria (E. coli) which was first noted in 1908 and 1980 respectively. Inactivation of viruses (Lions Sarcoma Virus) by fatty acids was reported in 1932, and later inactivation of enveloped viruses from different groups namely vaccinia, herpes simplex, influenza and African swine fever. Fatty acids with twelve to eighteen carbons are effective but PUFA’s were found to be even more effective in proportion to the number of double bonds available. DHA has 6 double bonds. No other PUFA has more. This is directly tied to the electron pi cloud and is the reason why DHA is linked to these immune effects. DHA also breaks down into resolvins, protectins and causes maresins to change macrophages from antigen presentation activators to anti inflammatory cells.

            In the human neuro-immune system omega 3 PUFA’s are converted by macrophage’s to an intermediate compound called 13S and 14 S epoxy-maresin. Maresins are produced by macrophages from DHA and they exert potent pro-resolvin and tissue homeostatic actions on the MHC1 proteins. These alter their action. Resolvins are compounds that are made by the human body from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They are produced by the COX-2 pathway especially in the presence of aspirin. This happens to be why aspirin is helpful in heart disease. No other reason. The aspirin effect is greater in men than women because men absorb more EMF than women to do electrify there DNA and protein water micelles that charge separate when they are adjacent to a hydrophilic protein. A protein is made hydrophilic by the ADDITION of electrons. Experimental evidence indicates that resolvins reduce cellular inflammation by inhibiting the production and transportation of inflammatory cells and chemicals to the sites of inflammation. Maresin’s promote the conversion of macrophages from M1 phenotype to M2 phenotype that specifically does not stimulate inflammation in the human body.

            1. http://www.ncbi.nlm.nih.gov/pubmed/21601924

            2. http://www.ncbi.nlm.nih.gov/pubmed/23504711

            Moreover, Martin Bailey at George Washington Medical School studied the effects of nineteen different viruses and reported that once a cell was infected and replication began there was a selective loss of delta 5 desaturase. These cells thus infected never regain that function and subsequently die. Fatty acids permit the virus attachment but prevent cell penetration to get to the nucleus to cause their damage. A number of fatty acids, particularly the unsaturated PUFAs have specificity against viral attacks, DHA more so than linoleic acid because it ability to collect and assimilate electrons when DHA is in the cell membrane of immune cells. http://journal.frontiersin.org/Journal/10.3389/fihttp://journal.frontiersin.org/Journal/10.3389/fi

            So when you can not put DHA in a cell membrane all hell breaks loose. IT is tied to most neolithic disease generation. It also points out why DHA has never been replaced in 600 million yrs of evolution. Its 6 allylic double bounds are irreplaceable. http://www.ars.usda.gov/SP2UserFiles/person/4986/set4/Final%20DHA%202012.pdf

          • Jack Kruse

            DHA deficiency (of marine fat) in the developing brain restricts migration of cortical neurones.

            Yavin E., Himovichi E. and Eilam R. (2009) Delayed cell migration in the developing rat brain following maternal Omega 3 alpha linolenic acid dietary deficiency. Neuroscience 162, 1011–1022.

          • Jack Kruse

            Bazan NG.

            Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection.

            Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2- 3):205-11

            I trained at LSU with Bazan.

          • Jack Kruse

            The rate of cellular lipid peroxidation increases exponentially with the number of bis-allylic positions. Brett A. Wagner, Garry R. Buettner, C. Patrick Burns JBiochemistry 1994, 33, 4449-4453 IT IS NOT ABOUT GRASS FED MEAT!!!

          • Jack Kruse

            The key point is DHA selected the proteins it can work with. the glycolipids in CM are the key piece. For example consider the eye heart or brain: di-DHA-phosphatidylcholine molecule viewed perpendicular to the plane

            Sites of build-up: Terminal N methyl group, CH glycerol carbon, and two terminal CH3CH2-CH=CH groups. Note remaining double bonds are planar. (CH3)3-N has a partial +ve charge, and the two CH3CH2CH= groups have a partial more negative charge, a mechanism exists for polarization to build up above and below the plane with the potential for Semi-conduction changing light into electric charge that be carried on CM, water, or the collagen cytoarchitecture in cells to perform coherent long distance signal in the CNS and PNS or anywhere where DHA is in a CM. Further investigation is needed to test this through out the rest of the body but we already know it happens in the retina. The retina has more DHA than the brain because blue light destroys DHA in CM. It has to be replaced and when it is not you get many eye diseases like cataracts and macular degeneration and pseudo tumor cerebri. All are circadian diseases due to excessive blue light in a system that is lacking DHA in CM.

            The excitation of a pi- electron in DHA is an attractive addition to any CM because it can take light to electric current or vice versa. This is why an altered plasma or membrane can lead to physiologic tissue changes and why all studies show DHA helps physiologic function. They make us energy efficient. We need a constant source of DHA to maintain this ability everywhere in our body. Calculations indicates the potential of the molecule to respond to visible light is possible and the recent findings on how rhodopsin works with photons bears that out. Rhodopsin rotates its bonds a specific amount with the addition of photons to cause protein confirmation changes in the photoreceptor which generates the post synaptic potential. DHA is the photoelectric transducer of all this.

            • At the synapse, the hyperpolarized membrane may be sufficient the suck an electron out of orbit.

            • Examples of this activity would be the DHA involvement in signalling in hippocampal cells in the brain and cardiac myocytes in our conduction described by Alex Leaf.

            There is a deep quantum reason DHA is highly conserved in all phylla since the cambrian explosion…….and in their cell membranes and it seems to select the lipo proteins it works with. That is why lipoproteins in CVD are all tied to this fascinating story.

          • Jack Kruse

            The only thing better than electrons for health is photons. Got electrons, you got health. Add in a photonic energy boost and you get Optimal.
            The electron dance makes the proteins of life come alive and dance with joy. Without electricity your coffee maker makes no coffee. In cold you preserve your charge on your batteries. When charge drops, oxygen drops, and you drop from disease.
            Photo-electric exchange is an indisputable scientific principle, not a theory, according to a dude named Einstein.
            An electron-rich body charge encourages oxygen to penetrate cells, prevents junk molecules from sticking to cell membranes and DNA base pairs, vanquishes pathogens and powers our immune cells.

          • Jack Kruse

            Solar energy enters the nervous system directly through the eyes and activates genetic expression directly by regulating the resonant frequency of DNA. This is called optical electromagnetic resonance. MRI, PET scanners and your pineal gland use it. Both the pituitary and pineal glands are also stimulated directly via optic nerve fibers. 2,000 years after solar gazing techniques were removed and disallowed by the early church, we were taught to fear the sun. Today dermatologists have replaced the Pope’s decrees. There is new interest. Quantum mechanics has proven that dissonant blue light frequencies with their excessive EMFs from indoor lighting will disrupt DNA vibrations and your nervous system.

          • Jack Kruse

            It is just not well known……in ancestral health or allopathic medicine. I am going to crash both parties.

          • Jack Kruse

            The role of polyunsaturated lipids in

            membrane raft function William Stillwell

            Department of Biology, Indiana University????Purdue University, Indianapolis, USA Abstract

            Docosahexaenoic acid (DHA), with 22 carbons and six double bonds, is the longest, most unsaturated fatty acid commonly found in humans. It represents the extreme example of an omega-3 (n-3) polyunsaturated fatty acid. Since early epidemiology studies, DHA has been linked to alleviation of an enormous number of human afflictions, including heart disease, cancer and neurological disorders. How one simple molecule can affect so many seemingly unrelated abnormalities has been a contentious question for many years. One research direction has investigated events that follow the uptake of DHA into animal cell plasma membrane phospholipids. Summarized here is a variety of membrane properties impacted by the incorporation of DHA. DHA’s dynamic shape, consisting of multiple configurations, is very different from what its static, stick structure would indicate. DHA-containing phospholipids have a wide hydrophobic base compared with their hydrophilic head and so induce negative curvature strain that severely impacts the activity of a variety of important membrane proteins. The unusual structure means that DHA-rich membranes are also surprisingly thin and support high permeability, compression, fusion and flip-flop rates. DHA does not exist in an environment that is independent from other membrane lipids. Of particular interest is the interaction of DHA-containing phospholipids with the major lipid raft components cholesterol and sphingomyelin. From a wide variety of biophysical studies, primarily done on model lipid monolayers and bilayers, a new hypothesis is proposed suggesting that DHA may alter plasma membrane lipid raft structure and hence essential cell signaling events. A fundamental role for DHA affecting a feature common to all cells, membrane structure and function, may explain its wide variety of reputed health benefits. BOOM! Lots of reasons DHA is the key to lipoproteins…….and electrons.

          • Jack Kruse

            Annexin A2 (ANXA2), a member of the annexin family of cytosolic Ca2+-binding proteins, plays a pivotal role in vascular biology. Small amounts of this protein and S100A10 protein are exposed on the surface of endothelial cells (ECs). They control fibrinolysis by recruiting tissue-type and urokinase-type plasminogen activators from the plasma. Nutritional studies indicate that two major long-chain polyunsaturated fatty acids (PUFAs), i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), provide benefits for EC functions. The effects of EPA and DHA on the plasminogen/plasmin system have not been characterized. These results suggest that EPA and DHA reciprocally control cell surface location of ANXA2. Moreover, cleavage of this protein by plasmin likely resulted in autodigestion of the platform for formation of this protease. In conjunction with termination of the proteolysis by rapid inactivation of plasmin by ?-2-antiplasmin and other polypeptide inhibitors, this feedback mechanism may emphasize the benefits of these PUFA in regulation of the initiation of fibrinolysis on the surface of ECs. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085045

          • This Old Housewife

            DHA controls the inflammatory process and epigenetic switches so they work well.

            This must be why I have an inflammation score of .25 in spite of having rheumatoid arthritis since the age of 3. I’m now 52.

          • “When incubated with human blood, AceDoPC behaves closer to lysoPC-DHA than PC-DHA in terms of binding to plasma albumin” …given their structural similarities, this isn’t unexpected. From 30,000 feet, which is analogous to the specificity of albumin for lipids, AceDoPC must look like lysoPC-DHA (sn-2).

          • Krill oil: “For the PtdCho class, ~58% contained a single n-3 FA, and 10% held an n-3 FA in both sn-1 & sn-2 positions. Of the species in the lyso-PtdCho class, ~35% contained an n-3 FA.” http://bit.ly/1iVJ2zG

            Assuming “lyso-PtdCho” is referring to the physiological (sn-2) isomer, this would suggest that the n-3’s in Krill are equally distributed among the sn-1 & sn-2 positions in PtdCho….

          • “This study provides evidence that n-3 PUFAs activate cognitive function in the elderly. This is especially the case with krill oil, in which the majority of n-3 PUFAs are incorporated into PC, causing it to be more effective than sardine oil, in which n-3 PUFAs are present as TGs.”

            http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789637/

          • “..arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid, might themselves regulate neuronal membrane excitability by blocking voltage-gated sodium and calcium channels, reducing inflammation through activation of peroxisome proliferator-activated receptors, or inducing expression of mitochondrial uncoupling proteins which reduce reactive oxygen species production..”

            So, whale eats krill, I should eat whale.

            –> http://journal.frontiersin.org/Journal/10.3389/fphar.2012.00059/full

          • Jack Kruse

            there is a point Ivor……..coming. Stick with me.

          • Jack Kruse

            The methylene interruption of the ?-electrons is crucial. It denies the copper wire like electron transfer in a conjugated sequence (think PrP now)

            (-CH=CH-CH=CH-CH=CH- ) as in retinal. In the conjugated system, the ?-electron clouds can overlap allowing electron (current) flow.

            However, the –CH2- is an electrical resistor but its

            Polarization in DHA is critical and offers a plausible key to the uniqueness of DHA in signalling in a membrane. And that place on the glycerol back bone is huge………Sn1 position is where DHA is on most food sources. To get it into the brain and CM it needs to be on the Sn 2 position to WORK.

          • Jack Kruse

            Why? The pi-electrons on the CH=CH groups are localized by the presence of the
            –CH2– barriers. The classical notion of such an energy barrier conjures a notion of a brick wall over which you have to have enough energy to jump over it.

            However, in quantum mechanics there is no such wall. There is only an electromagnetic force holding electrons in orbit and a probability of its location. Hence there is a probability that it will penetrate the barrier.

          • DHA is also more resistant to oxidation in the sn-2 position http://bit.ly/TP1XjD

          • Fish oil pills also lack the vitamins, minerals, protein, etc….

          • Can’t remember where but I think I brought it up once upon a time…

            I try to eat fish/shellfish 3-5 times a week – mostly wild caught salmon, prawns, squid, and oysters – but what do you think of the evolutionary unlikelihood of us ever having really eaten “deep sea” varieties, which tend to dominate our seafood choices nowadays?

          • Jack Kruse

            Ash in the beginning chimps isolated from the forrest in the East African rift that sits on 3 techtonic plates…..we ate shallow seafood like shellfish and crustaceans…….as we got smart we ate different seafood when we ran out of the shallow foods and began to fish. The deep sea fish are the predators and have the lowest amounts of DHA. Oyster the most. In fish sardines are the best option and this is the fish the predator fish eat to get their DHA.

          • Jack Kruse

            This links directly to the work of Chris Ramsden on chronic pain, diabetes, and excessive omega 6 and 9 blocking out DHA in cell membranes. When this happens chronic pain is the result. This is fundamentally why T2D all get restless leg, and neuropathy. People seems to forget oxidation from any source destroys DHA in CM and the metabolites of DHA are resolvins and protectins that favorable alter M1 and M2 macrophages. These macrophages are the major switch point of inflammation vs anti inflammatory pathways between the O6 and 03 PUFA’s. They are not created equal. It also points out why humans need a constant source of DHA in the diet to maintain this intricate balance in CM everywhere. This also is why every study links 03’s with lower inflammation and health. Clinical medicine knows these facts but have no idea how they connect and link for proper lipid raft function in cell membranes

      • Jack Kruse

        Joshua is getting the essence of Pollack’s findings. DHA makes lumens more hydrophilic. In fact anything that reduces proteins makes them more hydrophilic and this scales to the size and shape of lipoproteins to alter their thermodynamic properties. This is why there is correlation in particle size and not causation. No one seems to understand that sdLDL and HDL is tied to electron collection in the plasma and at the leptin receptor in the hypothalamus to tie hydrophilic abilities to thermodynamic consequence. Dr. Gilbert Ling, Dr. Gerald Pollack, and Dr. Paul Heroux are the only three I know who have. It is time medicine follow their data and not our current beliefs about heart disease.

    • Jack Kruse

      The things that open the door are vast. Oxidation due to a lack of electrons make proteins inside vessels more hydrophobic. This makes cholesterol streaks more hydrophobic and this decreases the exclusion zone of plasma within the vessels. This happens by increasing the ROS inside the plasma. When the EZ of plasma is altered it raises RNS in the cells lining arteries and this further opens the door of the endothelium. This is all mediated by calcium efflux and calmodulin alterations brought about by the loss of reducing power of the plasma. When this happens it changes the shape and protein conformations of the lipoproteins and this changes their physiologic abilities because it alters their thermodynamic abilities.

  • George

    From a public health perspective it is necessary to rewrite the current heart healthy diet prescription, even if you believe it works.
    Wherever there is a decline in cardiovascular mortality among people avoiding the traditional risk factors of cholesterol and animal fats (usually a small decline if any, unless we include studies with motivated and relatively privileged vegetarian volunteers) these is a corresponding increase in death from other causes, so that there is no net effect on total mortality.
    This means that when heart-healthy diet guidelines are prescribed to people at low risk of CAD (as in population wide recommendations) those low risk people will have a higher death rate and more non-CAD diseases. Diabetes, depression, cancer and so on. The contribution of any one of this increases to the death rate increase is small, but together they cancel out any benefit in terms of CAD.
    The simplest plausible explanation for this increased non-CAD death rate is a degree of malnutrition caused by lack of animal foods. (adverse effects of high-carb diets, grains, oils also apply to most people eating animal foods in studied populations).
    In this case it is an important public health undertaking to identify a heart-healthy diet that does incorporate sufficient fatty animal foods to benefit the whole population.

  • What sort of carbs did Krauss use for the high-carb diets in his studies? In http://ajcn.nutrition.org/content/69/3/411.full.pdf , 50% of the 75% carb content (i.e. 37.5%) is sugars. No wonder the particle size went to crap.

  • What’s not “PUFA and n-6 dietary fat?”
    Monounsaturates!

    What’s not high “glycemic index?”
    Low glycaemic index!

    RE Krauss et al 2006:- In http://ajcn.nutrition.org/content/83/5/1025.full.pdf , at the bottom of Table 1:- “carbohydrate, 50% simple and 50% complex;”
    The high-carb diet contained 27% sugars. I call Shenanigans!

    • Purposelessness

      Yes, krauss et al are obviously out to smear high carb diets by including sugar. No free living SAD eating human would ever consume half their carbs as sugar, totally outlandish.

      That said, studies with 100% starch as carb would certainly be interesting. Even if it’s only to see Nigel fervently commenting that the starch wasn’t low GI enough, saying that the authors of our hypothetical study undoubtedly where rigging the study against starch

      • Are you feeling better? Do you understand the point that I was making? Your ramblings about the SAD suggest not, so I’ll explain.

        I am pointing out every instance where eejits conflate “carbohydrates” with “sugars”. ‘Cos, y’know, all sugars are carbohydrates, but not all carbohydrates are sugars. Jeez!

        Do you get it, now?

        • Purposelessness

          No, sorry, I’m afraid I don’t understand. My rambling nature renders me unable to parse your incredibly clear and succinct writing.

          In fact, I’m sure you are the only one who understands anything, everyone who doesn’t agree with you clearly misses the point.

          You can also see who has a point and who has not by how you are the only one around here who manages to write a comment without using thinly if at all veiled insults. My my what an unruly mess all the nefarious cheaters are.

          • Congratulations! You’ve finally reached your nadir. And so soon, too.
            http://scienceblogs.com/startswithabang/files/2009/08/disagreement-hierarchy.jpg
            Have a nice day.

          • Michael

            I’m totes with Nigel Krimbum here. What’s with the aversion against sugar? There’s nothing wrong with it in moderation, and it’s a clean burning fuel, too, according to experts like Peat.

          • Shhh! Language like that isn’t tolerated around here. You almost got my name right.

          • Colin P. Müller

            Reign in your autism, please. Thanks, Nige.

  • Bill, I enjoyed reading. Looking at plaque might be an interesting new endpoint. We do CIMT’s with carotid ultrasounds in the office. Interesting the IMT thickness test does not seem to correlate. We see “old” blood vessels with no plaque and we see “young” blood vessels with lots of plaque. So we just look for plaque within the lumen to get a historical picture of atherogensesis.

    We are doing a lot of advanced cholesterol testing in our office including inflammatory testing. Addressing nutrition, cholesterol quality, oxidation etc… What to do when LDL-P rises in some despite large particles? Do nothing, reduce saturated fat, prescribe statins or ezetimibe.

    “The links between particle composition and disease outcomes are correlations.” Will we be able to prove causality?

    Great info and comments.

    • Thanks, Dr. Gerber. We’ve been studying this for a *long* time, and still don’t have many concrete answers…

      I’d be hesitant to reduce sat fats, for example, because of this study, where they were correlated with the smallest decline in CIMT over 3 years: http://www.ncbi.nlm.nih.gov/pubmed/15531663

      • That study is one of 64 (just counted) that I have tucked away along similar lines.

        Ash ? Sat Fats 4eva

      • Semi O/T – the other night I went to a panel discussion which was meant to be a science discussion on “Sugar vs Fat”, it was nothing of the sort, mostly just a grandstanding and pontificating of the failure of public policy and edumacation.

        Anyhoo, one of the panelists was Manny Noakes, the name sounded familiar, she’s from CSIRO here in Adelaide and it was only the next day I was skimming some of my Zotero library that I saw some of the studies on sat fat etc she was involved with, I’m sure many folk here have been exposed to them at some stage.

        #coolstorybro

      • Bill, here is another study looking at small particles and CIMT in diabetics:

        http://www.metabolismjournal.com/article/S0026-0495(07)00020-0/pdf

        • Thanks for the link.

          Given the close correlation between sdLDL and insulin resistance, I’m a little surprised the association between IR & CIMT was so weak.

          for anyone following along… full text: http://bit.ly/1pX7rW0

          • Guest

            Bill, yeas a nice correlation between sdLDL and insulin, not sure about the CIMT. CIMT correlates with blood pressure control and taking a statin, but not with CV risk directly.

            More on Questioning the Predictive Role of Carotid Intima–media Thickness. I do this test in the office along with a limited doppler. I like the limited doppler, looking for plaque within the lumen as the risk marker.

            I also question the role of EBCT calcium scoring and its’ predictive value, short of doing a CT angiogrm and or angiogram.

            http://www.medscape.com/viewarticle/750850_1

          • Bill, yes a nice correlation between sdLDL and insulin, not sure about the CIMT. CIMT correlates with blood pressure control and taking a statin, but not with CV risk directly.

            More on Questioning the Predictive Role of Carotid Intima–media Thickness. I do this test in the office along with a limited doppler. I like the limited doppler, looking for plaque within the lumen as the risk marker.

            I also question the role of EBCT calcium scoring and its’ predictive value, short of doing a CT angiogrm and or angiogram.

            http://www.medscape.com/viewar

          • Bill, yes a nice correlation between sdLDL and insulin, not sure about the CIMT. CIMT correlates with blood pressure control and taking a statin, but not with CV risk directly.

            More on Questioning the Predictive Role of Carotid Intima–media Thickness. I do this test in the office along with a limited doppler. I like the limited doppler, looking for plaque within the lumen as the risk marker.

            I also question the role of EBCT calcium scoring and its’ predictive value, short of doing a CT angiogrm and or angiogram.

            http://www.medscape.com/viewarticle/750850_1

          • Jack Kruse

            I’m not…….

    • Jack Kruse

      Dr Gerber you might be shocked to learn that Gerald Pollack has experimentally shown that acoustic waves like ultrasound waves cause a reduction in the exclusion zone of water which radically affect the energy in the plasma adjacent to a plaque. This will make carotid ultrasounds not really as accurate as we believe in medicine. I stopped using it in spinal and brain surgery because of what I learned from Pollack. Few clinicians seem to know about this effect. You should read his new book called “The Fourth Phase of Water” You need to realize there are other ways of looking at this. Consider the following as an example. We should not rely on just one method or mechanism of understanding things we do not yet fully grasp. Instead, why not intentionally use multiple means to formulate our truths? From the life experience of most of us, we recognize that there are multiple means or methods by which to apprehend the universe and beyond. One, of course, is rationality—examining the detectable, i.e., what can be analyzed by experiment. Here keen observation, focused attention to detail, reference to past experimentation, imagination, deductive reasoning and linear, logical mental processes are the tools—all of which are utterly indispensable to a potentially enlightened society.

      Nevertheless, remember, as the Einstein’s equal, Eugene Wigner, famously pointed out in an essay, experiment is set up subjectively by the questions the experimenter asks, and by the tools chosen to measure. Medicine has lost this idea completely. Researchers even more so. We need to be aware of this insight of Wigner.

      Humans see what they look for. The belief that science is experimentally grounded is only partially true. MD’s and Phd’s find this hard to accept but it is been proven by quantum mechanics time and time again. Rather, our intellectual apparatus is such that much of what we see comes from the glasses we put on. Eddington [Arthur Stanley Eddington; 1882-1944] went so far as to claim that a sufficiently wise mind could deduce all of physics, illustrating his point with the following joke: “Some men went fishing in the sea with a net, and upon examining what they caught they concluded that there was a minimum size to the fish in the sea.” Eddington was the astronomer who gave Einstein the photographic plates that proved that light bent around the sun to cause Mercury’s perihelion. This proved that Einstein’s thought experiments were validity on a cosmological level. He validated the theory of relativity. Something to ponder.

      • You’d love De Bono’s Lateral Thinking concept…it’s a kind of “demolishing pattern thinking”

  • valerie

    Is there a qualitative difference between LDL and HDL?
    Or is it a continuum?
    For instance, would very small, very dense LDL be HDL?

    • HDL and LDL are different in many ways, including their protein composition and functions.
      VLDL, LDL, and sdLDL, on the other hand, are closer to a ‘continuum.’

      • George

        IDL can be a both product of VLDL, and a hepatic output separate from, and instead of, VLDL – is this correct Ivor or Bill? And, if so, would these 2 IDLs then be the same thing?

        • ..my understanding is that VLDL is main hepatic output, but IDL and LDL also – for hypertriglyceridemic cases there is a greater proportion of the output in VLDL form, and considerably less IDL…..not sure diff between VLDL-originated IDL, and direct hepatic produced IDL – needs further review(!)

          • Liver secretes VLDL. IDL and LDL are formed in the circulation.

        • in general, IDL is formed in the bloodstream from VLDL…

          There is likely a spectrum of VLDL lipid compositions, but they’re still “VLDL.”

          • yep bill and I certainly stuck to that when going through the lipo processing in the vid; just the same I came across several papers that detail more direct hepatic production of IDL/LDL (and named as such) – simply never had time to go down this hole (not needed for primary root cause thrust at the time) – I just accepted it as yet a further increase in the “exquisiteness index” of the system! – one snippit below:

  • Diets high & low in GI… no effects on LDL-C and LDL-P.

    http://www.ncbi.nlm.nih.gov/pubmed/10403584

    http://bit.ly/1mfyVjR (pdf)

    high-GI diet: wholemeal bread, high-GI cereal, and high-GI fruits & veggies

    low-GI diet: wholegrain bread, low-GI cereal, and low-GI fruits & veggies

    total carb, sugar, and starch intake was similar.

    no effect on LDL cholesterol or particle size… in combination with the studies cited above, suggests total carb, not simple/complex is a more important factor (?)

    • Rakesh Patel

      the elephant in the room

    • Jack Kruse

      Bill the effect is a combo effect of water upon lipids and the carbs/proteins they allow to incorporate. DHA incorporation is tied to the hydration and salinity of the plasma. Once DHA is in the CM then it selects the glycoproteins it will work with. The lipids intrinsic physical electric and magnetic potential select the proteins and carbs they need to act properly to decipher signals. I know you are well acquainted with Crawford’s paper on DHA dictating evolutionary design of carbs and proteins in cell membranes. Now let us take it to the CVD level. Why is cholesterol so misunderstood in heart and PAD? The polar nature of both water and cholesterol molecules allows them to bond to each other in lipid rafts or groups. Cholesterol needs electrons to remain polar. It charge changes tremendously when it loses electrons from DHA’s pi electron cloud or from water. CM all are adjacent to water in a cell. Being polar allows it to remain hydrophilic to generate a large EZ. When it is oxidized it can not. Proton flow in the plasma ceases and this causes BP to rise. Proton flow in the center of an hydrophilic artery flow is augmented by the EZ. Once Again, Gerald Pollack’s experiments prove this mechanism occurs in hydrophilic tubes. This is how BP is augmented to lower left heart pressures and how capillary flow occurs. Cholesterol works ideally in this state and not in its oxidized state
      Remember brains and all cell membranes ARE basically made of fat and, as such, generate/store electron charge naturally. Sulfated proteins attach to these saturated fats and produce voltage when they bind to the polar cholesterol molecule! So when cholesterol levels in the brain are lowered, voltages drop tremendously. Neurosurgeons and neurologist see this daily on EEG’s of those with carotid disease, CVD, and neurodegenerative diseases. All tied to a failure of redox chemistry. This is why medicine is broken. No one is looking in the right place because they do not understand the biophysics involved.

  • Jack Kruse

    Bill nice blog. Particles size correlates to the redox movements in the liver and in the plasma in response to those additions of subtractions. This alters lipoprotein sizes and mass according to thermodynamics and mass equivalence. When things lose energy anywhere in the universe they expand……supernova, people, and lipoproteins. The key missing link to all this science is that oxidized cholesterol changes the inside of an artery from hydrophilic to hydrophobics. This is where plasma zeta potential (electron density) begins to alter protein conformations. This is where the rubber meets the road for lipoprotein changes under compliant design changes due to the loss or gain of electrons. It is also a cross roads of where atherosclerosis begins. When the arteries become hydrophobic due to electron loss, there is less proton flow flow in blood and BP must rise to offset the loss. Pollack’s work showed fundamentally why this happens in hydrophilic tubes. It decreases the EZ of water flowing in the tube. This changes the amount of electrons avaliable to cholesterol and lipoproteins. The law of mass equivalence scales everywhere in the universe. Few realize it.
    How electrons work in mitochondria, which are derived from food seems to offend the “common sense of biology.” I find this concept to be a very good thing because the the principles of relativity, quantum mechanics and quantum vortices in black holes also offend biology. This is the way nature works in us, and across the whole universe.

    • Saturated fats = electron dense!

      On another note, I had a fun time explaining the difference between electron density and buoyant density during my dissertation.

    • Timar

      Sorry, but everything this guy writes here sounds exactly like the driveling of a (megalo)maniac.. as it it were straight from the psychology textbook.

  • Sorry Bill, you’ll have to retcon the version number of your article, according to Kurt Harris back in 2010 we were already way beyond:

    –> http://high-fat-nutrition.blogspot.com.au/2010/03/butter-insulin-and-dr-davis.html?showComment=1269113971352#c4657578845003911394

    “I think even referring to chylomicrons or pp TGs in any form as a “mess” is sort of buying into the Lipid Hypothesis version 5.0.”

    😀