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Oct 08

Guesting on the Peter Attia Drive – Response to Peter’s Prebuttal

Peter included a prebuttal at the beginning of his podcast with me that included three central points. I’ll take them one by one.

The first:

Dave was unable to explain the mass balance, meaning how does one account for the greater amount of cholesterol in, and the greater number of, LDL particles. No one, including Dave, is disputing that the phenotype of interest has more LDL-C and more LDL-P. There are only 3 ways this can happen (these are [collectively exhaustive, but not [mutually exclusive]): make more, clear less, transfer from other pools that we can’t see (e.g., cell membranes). I think the data make the first of these by far the most likely driver, but Dave seemed unable to address this and could not explain, to me at least, what could account for this increase in LDL-P/C. So on first principles, my doubt of this model has gone up from the start of this discussion, as the person who developed the model could not actually explain the mass balance. This is one of the most fundamental requirements of any model. And to be clear, even if this fundamental condition were met, it would not be sufficient to make the case that [lean mass hyper-responders or LMHRs] are not at risk. It’s a [necessary but not sufficient] criteria that, in my mind, has failed.

Let me first start with the analogy I used in the podcast of boats/life rafts and walk it all the way through:

  1. There’s a harbor with 100 boats that are regularly leaving to deliver cargo to a far away island before returning again. Each boat has 10 life rafts onboard. Thus, we have 100 boats and 1,000 life rafts “in circulation”. There’s no boats being removed or life rafts taken off in this example for illustration purposes.
  2. There was first a period where they were built that required more mass (materials for building = mass). But once in circulation, there’s no requirement for further addition mass.
  3. After a while, the demand changes on the island and more cargo is needed to be delivered, this will require 500 boats. Construction material for these boats are required, but just enough for 400 more. And more life rafts are required, but just 4,000 more. More mass is needed in this phase to meet demand for more boats in circulation. But once in circulation, there’s no more mass needed.

So yes, there’s both more creation of the boats and recirculation of the boats. The problem comes when trying to determine how much there is of each from only seeing them in the water alone. One can’t look at the 100 boats (or their life rafts) or the 500 boats (or their life rafts) while in circulation and draw a conclusion on mass balance. Indeed, in this example, once each batch is built, there’s no further change in mass balance, only ongoing recirculation.

I don’t think Peter disputes the liver’s cholesterol pool is fungible and that lipoproteins and their cholesterol cargo are continually reabsorbed, rebuilt and/or reused. There’s still much being learned as to how much, but I doubt anyone would argue it’s very dynamic. But the recirculation is especially important to acknowledge as a relevant component of the overall metric.

Hence, this is why I eventually asked this question of Peter during the podcast when we seemed stuck on this point:

“How much of this cholesterol has already made a lap? Are you thinking of this in terms of it all getting synthesized and then reabsorbed, and then recreated it again?”

If I’m understanding his position correctly — he believes either that lipoprotein cholesterol isn’t making any “laps” (re-sent again in another lipoprotein) or that it is a fixed number of total trips. How else can we not assume this is relevant toward the total balance?

In other words, this suggests the lipid pool within the lipid system is not ultimately fungible from a lipoprotein transport perspective, and that reuse/recirculation is actually limited in a predicable way.

If so, this is certainly a point we’d disagree on.

 

<Special note: If Peter would like to add clarification or rebuttal to the above response, I’ll include it here>

The second:

Dave argues that VLDL production is driving the LDL concentration, but the fact remains that in insulin-sensitive people (which presumably the LMHRs are), the opposite is true: there are fewer, not more, TG being exported from the liver and there is less, not more, apoC-III on the VLDL, thereby reducing, not increasing, their residence time. In other words, LMHR would have less VLDL to LDL conversion than, say, someone with T2D. So again, I can see no evidence whatsoever that his energy model, which can’t be explained on mass balance, and can’t be explained on what is known about the physiology of VLDL and LDL, is plausible.

As per the podcast, I was very up front on this being theoretical. Indeed, I qualify this very early:

Dave Feldman

“With that in mind, here’s what I would speculate. This is purely hypothetical, but I would speculate if you were to grab a whole bunch of people who are … We’ll hopefully get into this model that I’m talking about, that I call lean mass hyper-responders. People who are at the far end of the spectrum, they are athletic, they are thin, and they are very, very low carb, and therefore see very high levels of LDL-C and LDL-P, but they also have very high levels of HDL-C and low levels of triglycerides.

I suspect that they would show a very high rate, proportionally, of VLDL secretion, that they actually are trafficking a lot more, for their energy, triglycerides in VLDL particles, and therefore have succeeding LDL particles as to the explanation as to why their LDL-C and LDL-P would be higher.”

What I’m more interested in is how one can be confident in the opposite. How do we know there are fewer TG “being exported” from the liver in healthy hyper-responders, for example? If we can be, than he’s right, that would put a dent in my theory.

But don’t confuse a blood test for TG as an indicator of TG secretion by the liver. Again, you have to realize the other side of the ledger with uptake by tissues. This is why the three lowest TG blood tests I’ve ever had were following half and full marathons. We wouldn’t confuse glucose entering the bloodstream with glucose found in a blood test for the very same reason — uptake matters.

So without question, I’m extremely interested in any kinetic studies that would involve capturing TG secretion from the liver (aboard lipoproteins, of course) in payload comparisons between healthy hyper-responders vs healthy controls. And I definitely speculate the former would have higher overall TG secretion, yet likely higher TG use as well. But the “export” as Peter puts it, is certainly the key.

<Special note: If Peter would like to add clarification or rebuttal to the above response, I’ll include it here>

The third:

Even if you ignore the points above—which you can’t—I am more unconvinced than ever at the notion that we should exclude the roughly 2,000 genetic mutations known to produce a phenotype of high LDL-C, high HDL-C, and low TG. We have 2,000 natural experiments. Surely at least some of these cases (e.g., PCSK9 gain of function) are excellent proxies for the key features of LMHR. Yet to ignore them for imaginary reasons (e.g., having gain of function PCSK9 is somehow toxic to endothelial cells because it impairs their ability to take up cholesterol despite there being no evidence that endothelial cells require PCSK9 to uptake LDL in a receptor-mediated fashion) is to say, in my opinion, one does not want to know the answer to this question.

Before answering this, I’m reaching out to Peter to get clarification on his first sentence. I believe he honestly misspoke on identifying the triad that I’m interested in (high LDL-C, high HDL-C, and low TG) and instead simply meant LDL-C alone. To my knowledge, there’s no study that identifies the phenotype of that triad I’m interested in. (But if you know of one, please contact me!)

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Rob Monahan
Guest

Hi Dave,

I am following this very closely because I have some highly unusual numbers due to a complicated history which I’ll summarize here because based on all of my previous n=1 trials, I think your protocol may hold some valuable answers.

42 year old male, 9% bodyfat, active, hx of cancers (Leukemia, Thyroid Cancer, Bile Duct Cancer, Testicular Cancer); total body radiation age 7 (subsequent physiological changes presenting as secondary cancers and metabolic syndrome);

MI age 39.

Since my MI, I have been obsessed with particles and Insulin resistance. It is believed that I have adipocyte specific insulin resistance as my Hba1c is under 6, fasting insulin and glucose are highly controllable (last tests were 5 and 85 respectively). Normal Lp-PLA2, Lp(a), fibrinogen, CRP..haven’t had oxidized ldl or ADMA done.

On LCHF (no oils at all, moderate saturated fat) Ldl-p =1050, LDL Direct=90: small dense particles=800; Triglycerides=650 (yes, six hundred fifty); HDL=27; ApoB =111

On LCHF, high saturated fat and high oil consumption (coconut and olive) LDL-p fires up to 2500 range but no change in TG or small dense particles. ApoB=170

On very low fat, moderate carb (under 120 grams per day or carbs, spread out); LDL-p rises to 1500; small dense particles drop to 600; triglycerides 185 (lowest value in 35 years); ApoB=normal.

Constants: Kidney Function compromised (EGFR 40; Creatinine 1.7), homocycteine=20; testosterone supplementation (hypognadism from radiation)

Boston Heart Lab post MI showed highly elevated sitosterol and campesterol (both over 400) but I was on 80 mg atorvastatin at the time (virtually eliminating synthesis). No statin has any effect on TG, and all statins, including 1 mg pitavastatin, raise fasting blood glucose significantly.

ApoE: 3/3

Lipoprotein phenotype: 4 (chylomicrons absent, beta normal; pre-beta increased; alpha normal. TG were 1100 at time of testing …fasting.

Tom Dayspring mentioned several possibilities in a response to me, but with very limited information (based on knowing about low HDL, high TG with normo APoB)….. “Possible Familial Hypertriglyceridemia, familial or other chylomicronemia (LPL or ApoC-II issues), and some (not all) types of hypoalphalipoproteinemia”

Siobhan Huggins
Admin

Hi – unfortunately, any medication makes it difficult to spot any patterns because they introduce so many variables, and we don’t have a huge amount of experience in seeing what their profiles generally look like (just as a consequence of who comes to the site and who doesn’t).
To rule out two common issues though – were these tests all fasted 12-14 hours (no coffee or caffeine during the fasting period, water only)? And do you drink coffee regularly?

There is of course a possibility it could be genetic (As Dayspring implied), but I find it curious that chylomicrons are absent (e.g. presumably able to clear them effectively), and thus the triglycerides appear to be residing in VLDL alone.

But again, I can’t provide any solid conclusions in this case because it’s a context neither Dave nor I are used to seeing…

Rob Monahan
Guest

Hi, Thanks for the reply! I was fasting (water only) and do not drink coffee (mainly because I don’t care for it and it doesn’t help me in any way throughout the day.. I don’t outwardly feel the effects). I’ve been trying to learn the mechanics of IR but with there being unique effects of liver, muscle, adipose IR, compounded by things like the kidney function & thyroid and hormone replacement, I have trouble with the number of variables. My thinking now is that the adipose IR acts as a major driver in delivering a constant flux of fatty acids to the liver (that should have stayed bound in the adipocytes or that should have been used somewhere for energy in the absence or carbohydrate as an efficient energy substrate)..but I have not fully attempted a ketogenic plan for more than a couple of weeks..so I have always provided at least some carb for energy on top of the gluconeogenesis I see whenever I carb down.

I’ve also been trying to understand the role of liver IR in VLDL and TG packaging. I don’t see much in writing about the sizes of VLDL particles. If my Apo-B is normal and my ldl-p is nearly normal with direct ldl measurements under 100, I would suspect that the VLDLs must be very large to carry the TG burden (TG between 500 and 1000 at all times unless fasting more than 24 hours or eliminating fat from the diet. I am not on statins now but I know that they virtually eliminate my ldl count and drive the ldl-p very low without affecting the triglycerides in any way. I have a very very slight amount of steatosis, especially considering lifelong elevated TG, and no pancreatitis.

Anyway, Thanks for doing what you do and for this amazing resource. I have learned so much here.

Siobhan Huggins
Admin

My thinking now is that the adipose IR acts as a major driver in delivering a constant flux of fatty acids to the liver (that should have stayed bound in the adipocytes or that should have been used somewhere for energy in the absence or carbohydrate as an efficient energy substrate)..

As far as I understand it, this is correct. The IR in adipose can come about a few different ways, but ultimately the result is the same.

but I have not fully attempted a ketogenic plan for more than a couple of weeks..so I have always provided at least some carb for energy on top of the gluconeogenesis I see whenever I carb down.

I am wondering if this may be part of the problem, or at least a problem on top of another underlying issue. It can take 2~ months to get past the adaption period for a ketogenic diet, and lab results are often wonky before the 4-6 month mark. By adding carbs back into your diet (how much were you adding in? From what source?), you may be preventing fat adaption (forcing the body to rely on fat instead of glucose). I’m not sure how frequently you’re doing this but if it was somewhat often or near a blood test it may have shot trigs up due to impaired energy partitioning (having to deal with both glucose and fat, or just via never properly adapting). Or over all just odd results due to constantly capturing yourself in the adaption phase, paired with a possible genetic/other factor.

I’ve also been trying to understand the role of liver IR in VLDL and TG packaging. I don’t see much in writing about the sizes of VLDL particles.

I don’t think we have any posts specifically on VLDL size, but generally with IR you have larger VLDL as you said. I would expect your VLDL particle count to be on the higher end as well.

(TG between 500 and 1000 at all times unless fasting more than 24 hours or eliminating fat from the diet.

I likewise find it interesting that trigs go down upon multiday fasting, how far do they go down? Did you have other tests done when multiday fasting to compare to a 12-14 hour fasted test? I would be curious to see what changed between those two tests if you have them.

I am not on statins now but I know that they virtually eliminate my ldl count and drive the ldl-p very low without affecting the triglycerides in any way.

I think this is generally(?) the case with statins as far as not moving trigs much. If you’re not currently on any medications now, and are intending to stay like that for a little bit, perhaps a re-test would help see what your levels are “normally” (unconfounded). Were/are you on any other medications beyond statins that could possibly interfere with lipid metabolism? (Fibrates, niacin, etc)
Some additional tests (insulin, hs-CRP, B12 and folate, NMR lipoprofile, CBC, CMP) could also help provide additional context as well.

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[…] Update 2 – 10/8/2018: I now have a response piece to Peter’s prebuttal at the beginning of the podcast which you can find here. […]

Shaza
Guest
Shaza

HI Dave, I thought you did a wonderful job on Attia’s podcast, but I found it very distracting with Attia’s combative posture and arrogance. YOU were ever the gentleman and were filled with curiosity for the subject and for what Attia was saying. 3 hours of listening to ATTIA is TOOOO long, one can only take so much of paternalistic arrogance… funny because I liked him before this. He came across as though he was teaching you a lesson… keep up the good work, I greatly admire your humble curiosity and good manners! Shaza

Aino
Guest
Aino

Yes! Exactly my feelings too!! Well done Dave! It takes courage to go up against Peter Attia. I respect his intellect and what he does, but he did come across in this podcast as arrogant.

Alain Gueye
Guest
Alain Gueye

I felt exactly the same way.
And plus, a person that has to use cussings in order to get to his point or because he is frustrated, to me that’s not a good sign, and definitely he is not a person that I wanna listen to nor trust.

Colleen
Guest
Colleen

I have listened to the entire podcast but not read the transcripts/posts here. I admire both Peter’s work and your work, and that you are both putting it out there for the benefit of others. I have been following Peter’s blog since before his cholesterol series began and your blog for about one year since I learned of it. I fall within the LMHR category though probably because I am (now) relatively lean but not a heavy exerciser.

I was disappointed by the podcast. Peter did not carry out his discussion with you like his other podcast guests. My impression was he would not engage with you and your hypotheses unless you answered his questions using the most precise biochemistry vernacular — something he does not require at all times of other (Dr.) guests. The discussion seemed very choppy and never seemed to finish discussing one point before jumping to something else.

As someone who has never studied biochemistry formally, my impression of you was that you seemed to have some difficulty discussing some basic biochemistry of the cholesterol system. Listening to other talks by you are reading your posts, my impression is you have more knowledge than it sometimes appeared during this discussion with Peter.

By the end, Peter seemed to be getting agitated, whether by the theory in general or the seeming inability to connect on the same level with you it was not clear. At some points, he seemed to be talking about one idea and you another. [His response when you mentioned high HDL, high LDL, and low trigs and stratifying that data was perplexing, as I am almost sure he and Ron Krauss mentioned the triad and in passing alluded to this state and also discussed these 3 numbers], but I understand his ultimate position as he noted several times, he has to discuss with people what to do if they have high cholesterol but everything else looks good. I think the honest answer is we don’t know, but as a Dr. hard for him to ignore possibility of harm from this state (which he sees as more probable).

His insight about low carbers having learned to distrust science or standard guidance and this leads them to easily jettison the cholesterol recommendations I think is very true, but he seems equally biased in the other direction. I am still working on my own n=1 experiments, but if I wanted to hear the strongest case for lowering my cholesterol and/or medicating, I would definitely put Peter on a list of who to consult with. Unlike my own ex-physician, Peter is brilliant and has obviously thought about these issues unlike many (most?) docs just passing out the party line with little understanding of the recommendations.

My take away at the end of the day is that these lipid researchers have not actually considered the situation you have identified, i.e. LMHR, people on a low carb diet whose LDL increases, other numbers good, and the extreme ability to manipulate this system. Even if they understand that to be the case, no one has really studied this population and whether this is a healthy phenotype. If it has been studied, not even Peter or Ron Krauss have identified where it has been determined to be unhealthy. Until low carb became popular again in the last 15 years, and this “cohort” was identified via the Internet (healthy low carbers with high LDL) I wonder if anyone even knew the extent to which it would exist, especially in the lipid research context though certainly Drs. like Atkins and low carb researchers probably were aware?

I do like Peter’s suggestion to go to NLA meetings and make direct contacts, try some direct dialogs, as it seems a more likely method to peak someone’s curiosity and get some of these ideas considered in the context of ongoing research.

Greg
Guest
Greg

I concur with your opinion. I love Dr. Attia & his work but it really felt like a set-up to me. That said I’m new to Deve Feldman.

Man I just want the TLDR; on this topic haha. I need a safe protocol to follow because to find a doctor I can trust is not easy… never mind finding a leader in the field and not a statin pusher.

Amanda
Guest
Amanda

If the cohort had existed before then presuably there would have been a body of research on it, his doctor would have known of its existence, there would be an agreed – ” does this cohort require statins or not” and Dave could have carried on being an engineer! As it is it seems very likely that no-one has been looking in this direction before in any event.

Shaza
Guest
Shaza

Colleen, your post was everything I was thinking! Great comment. You saved me writing it all out! Shaza

Carol
Guest
Carol

I absolutely agree with previous comments. It was definitely a setup and Dave was not treated the same as Peters other Dr guests. Peter could barely disguise his contempt for the Bloggersphere. Very arrogant performance I thought and I was previously a fan of Peters work.

joel
Guest
joel

Aha I just wrote a very similar comment on Peter’s wall actually. I’m not sure how peter went so quickly from “the mainsteam has it completely wrong fat is amazing im sure of it” to “oh my gosh you dont know anything all my mainstream lipid friends are so cool” you guys are all conspiracy theorists lol.

Actually mostly I just like how he loves well-done studies; but I completely agree with Colleen in that in my opinion the studies he was pointing to were AT BEST talking about “insulin sensitive” people (not low carb). The data just isn’t there I don’t think at this point. and also i agree that Dave never said HDL was anything other than a possible marker at best- not sure why Peter lost it there lol

Andrew Cleveland
Guest
Andrew Cleveland

Thank you for the thorough and unbiased response, Colleen. It is refreshing to see a balanced and thoughtful response on a topic full of confirmation bias and tribalism from all sides.

Tim Foxon
Guest
Tim Foxon

Hi Dave, I posted this on FB earlier but it should be here also.

The objections posed by Attia can be answered as follows.

1. The first objection is …..“Dave was unable to explain the mass balance, meaning how does one account for the greater amount of cholesterol in, and the greater number of, LDL particles. No one, including Dave, is disputing that the phenotype of interest has more LDL-C and more LDL-P. There are only 3 ways this can happen (these are [collectively exhaustive, but not [mutually exclusive]): make more, clear less, transfer from other pools that we can’t see (e.g., cell membranes)……”. Here Attia is asking Dave to account for the dramatic increase in LDL-C and LDL-P.

2. The second is …. “Dave argues that VLDL production is driving the LDL concentration, but the fact remains that in insulin-sensitive people (which presumably the LMHRs are), the opposite is true: there are fewer, not more, TG being exported from the liver and there is less, not more, apoC-III on the VLDL, thereby reducing, not increasing, their residence time. In other words, LMHR would have less VLDL to LDL conversion than, say, someone with T2D. So again, I can see no evidence whatsoever that his energy model, which can’t be explained on mass balance, and can’t be explained on what is known about the physiology of VLDL and LDL, is plausible.” Here Attia is arguing that the LDL concentration being driven by VLDL production, which he says is Dave’s argument is not reasonable as the VLDL content in LMHRs would be lower and not higher thus leading to lower not higher LDL-C/P concentrations.

To assess the cholesterol changes in LMHR individuals and whether this is dangerous it is necessary to compare them to similar individuals (ie relatively high performance) but consuming a different (not keto) diet.

Fortunately, this is now possible due to a study recently conducted by Volek/Phinney et al.
http://sci-hub.tw/10.1136/bmjsem-2018-000429
#

This study compared a group of ultra-endurance athletes, some keto (a proxy for LMHR) and some high carb (a good control).

The primary outcomes were extremely large increases in the total, LDL and HDL cholesterol pools of the keto group versus the controls.

Although the reasons behind the cholesterol changes in LMHRs is not completely determined it does appear that the LMHR phenotype is a beneficial adaptation, both physiologically and clinically.

To Attia’s first objection.

The keto group had significantly higher intakes of saturated fat (86 vs 21 g/day) and cholesterol (844 vs 251 mg/day), and lower intake of fibre (23 vs 57g/day). All three can be shown to associate with an increase in cholesterol but this is a partial and not a complete explanation as the degree of change is not great enough. There are other things going on.

The first may be that dietary cholesterol is reflected more in the circulating cholesterol pool in keto-adaptation than in controls, this seems to be caused by an inhibition of the conversion of hepatic cholesterol to bile which normally limits circulating cholesterol levels in higher dietary cholesterol situations. Also, the fact that the overall ratio of cholesterol synthesis to absorption markers (ie, the fractional cholesterol balance) was the same between keto and control athletes is consistent with the fact that greater consumption of cholesterol by keto athletes is translated into an expansion of their circulating cholesterol pool. The second is that ketosis itself and higher lipid fluxes in keto may enhance cholesterol production by providing higher cytosolic substrate cholesterol through synergy in the cholesterol production process.

The substantially greater rates of lipolysis and fatty acid oxidation compared with their control counterparts may also require adaptations in intravascular lipoprotein metabolism to support the overall greater flux of lipid fuels. Serum HDL-C, specifically HDL2-C, raising effects of exercise are partially attributed to increased expression and activity of skeletal muscle lipoprotein lipase, which breaks down circulating triglycerides, resulting in a transfer of cholesterol and other substances to HDL-C. It is quite likely keto-adapted athletes increase muscle lipoprotein lipase to enhance use of triglyceride from circulating VLDL particles.

In addition there are common polymorphisms in successful endurance athletes that might contribute to a hypercholesterolaemic profile in the context of a ketogenic diet.

So to answer Attia’s question the extra comes from all three sources, for various reasons.

To Attia’s second objection.

The keto group had lower triglycerides with significantly less VLDL particles, much less large VLDL particles and smaller mean VLDL particle size. This paradoxically drives higher LDL particle number as smaller VLDL is much more easily delipidated to LDL and a smaller VLDL output and particle size in the liver is associated with more direct LDL secretion as opposed to VLDL secretion. In addition with heavy lipid demands and a smaller VLDL pool a larger LDL pool is needed for lipid delivery since the LDL particle has a smaller ratio of lipid to cholesterol.
https://www.ahajournals.org/…/10.1161/01.atv.17.12.3542

Clinically the changes were all positive for LMHR. This includes much better insulin sensitivity, smaller small/dense LDL pool, lower TG/HDL ratio and lower triglycerides. In addition the much higher HDL pool demonstrates greater uptake from tissue, including transport of reverse macrophage cholesterol, important in atherosclerosis.

Overall the keto-adaptation in LMHR appears to be a metabolic adaptation that is physiologically and clinically advantageous.

Cheers mate, keep up the good work.

Tim Foxon
Guest
Tim Foxon

Hi Dave for completeness the following should be included as I edited the FB post.

To Attia’s second objection.

The keto group had lower triglycerides with significantly less VLDL particles, much less large VLDL particles and smaller mean VLDL particle size. This paradoxically drives higher LDL particle number as smaller VLDL is much more easily delipidated to LDL (Thus, large VLDL was postulated not to form LDL to a significant degree, a tenet that has been confirmed by others.22 Rather, its delipidation ceases in the VLDL or IDL density ranges where it is thought to generate remnants that persist in the circulation for considerable periods (Fig 1). Intermediate sized VLDL of Sf 60 to 100 has kinetic properties similar to those of Sf 100 to 400 VLDL, although more of the apoB from this interval is delipidated to LDL.51920 ApoB containing particles in the Sf 20 to 60 density range, in contrast, are rapidly and efficiently converted to LDL with >50% of the tracer being observed in LDL within 24 hours after injection – see ref below) and a smaller VLDL output and particle size in the liver is associated with more direct LDL secretion as opposed to VLDL secretion (ApoB is made constitutively in the liver. Initiation of lipoprotein assembly requires the addition of a small amount of neutral lipid to the growing polypeptide chain. Further lipid is added during particle assembly and secretion and the nature of the final lipoprotein released (which ranges from LDL to VLDL1) depends on the extent of lipidation – see ref below). In addition with heavy lipid demands and a smaller VLDL pool a larger LDL pool is needed for lipid delivery since the LDL particle has a smaller ratio of lipid to cholesterol (This may be related to the apparent suspension of cholesterol to bile conversion).
https://www.ahajournals.org/…/10.1161/01.atv.17.12.3542

Clinically the changes were all positive for LMHR. This includes much better insulin sensitivity, smaller small/dense LDL pool, lower TG/HDL ratio and lower triglycerides. In addition the much higher HDL pool demonstrates greater uptake from tissue, including transport of reverse macrophage cholesterol, important in atherosclerosis. Also the higher cholesterol confers greater immunity.

Cheers.

Rob Monahan
Guest

Tim,

This info is really thorough and helpful. Thanks for taking the time to write it down and share it. Have you seen any research on the effect of Insulin resistance on skeletal muscle lipoprotein lipase? While the entire episode was of great interest to me, I am looking for answers from an insulin resistant perspective.

Tim Foxon
Guest
Tim Foxon

Hi Rob.

While I have not seen a direct link as I have not looked at that particular point I suspect there is one and I suspect, but can’t say for sure, that muscle lipoprotein lipase is enhanced in muscle insulin resistance. This accounts partly for the lower TG in LMHR. Part of the LMHR adaptation must include large muscle insulin resistance (physiological insulin resistance) while conferring whole-body insulin sensitivity. Insulin resistance is organ specific so it makes perfect sense the body would shift resistance to some organs while preserving sensitivity in others to accommodate glucose homeostasis and to accommodate lipid demands.

Tim Foxon
Guest
Tim Foxon

From my first post.
…..it is quite likely keto-adapted athletes increase muscle lipoprotein lipase to enhance use of triglyceride from circulating VLDL particles…..

So the connection to muscle insulin resistance is a natural one and the association is definitely there.

From the body’s point of view, it makes absolutely no sense to keep the muscles insulin sensitive as that would suck more glucose from plasma and from a limited pool, thus depriving the brain in periods of high activity.

This is seen in HC athletes and is called “hitting the wall” or “bonking” LMHRs don’t suffer this aspect of high activity which is yet another reason the adaptation is advantageous.

Stephen Thomas
Guest

This really is fabulous detail. Thank you for sharing it.

Kevin
Guest
Kevin

Hi Tim, interesting input. You link to the paper https://www.ahajournals.org/…/10.1161/01.atv.17.12.3542 doesn’t work. Can you provide the name and author of the paper?

Siobhan Huggins
Admin

It looks like the link broke, likely because it was copied from facebook which shortened it.
Going off of the doi, it is this one.
Lipoprotein Heterogeneity and Apolipoprotein B Metabolism – Chris J. Packard and James Shepherd

Tim Foxon
Guest
Tim Foxon

Hi Kevin, sorry, here is a link that works.
https://www.ahajournals.org/doi/full/10.1161/01.atv.17.12.3542

The paper is an interesting look at lipoprotein metabolism. It concentrates on the idea of metabolic channelling which I think is important but I never see discussed anywhere else.

Tim Foxon
Guest
Tim Foxon

BTW if you are interested there is a fairly good discussion on Dave’s LMHR profile resulting from a post I made speculating on what may cause it. You will have to join the LMHR group on FB.

https://www.facebook.com/groups/LeanMassHyperResponder/?multi_permalinks=333671750721198&comment_id=333701190718254&notif_id=1539562884540207&notif_t=feedback_reaction_generic

Tim Foxon
Guest
Tim Foxon

As a final note, I want to thank Dave and the team here for their salutary efforts. Dave’s work has considerably undercut the cholesterol fanatics in showing completely unexpected short-term dynamics. In particular, his identification of the LMHR phenotype is a dramatic revision of the mainstream belief in the dangers of “excessive” cholesterol and must now form part of the cholesterol debate if it is to be believable and honest. I predict that thanks to Dave fewer people will take statins and thus many will be saved from the debilitating effects.

Rob Raymond
Guest
Rob Raymond

I listened to the full podcast and was left with more questions than answers. I still need to read through this website, but it sounds like we are a long way from finding a definitive answer.

If the answer did come back to say that LCHF is not good in the long therm and I need to modify my diet I would really struggle with that because I eat LCHF to manage IBD and diabetes risk. Both are very serious and arguably are more problematic to quality of life in the short and long term.

Are there other tests that could provide some level of comfort that we as LMHR we are not heading towards CRD?

Should I ask for CAC scan and/or CIMT? Is there anything else?

I need a list of tests to ask my doctor for so that I can better track this.

Colleen
Guest
Colleen

Rob: You are right, no definitive answer in the near term, especially if all researchers with Peter’s mindset. I think the key is to study your inflammation picture. If you have low inflammation, it appears unlikely or much less likely that high LDL is going to cause any problem. So, and I think this was referenced in passing, blood pressure. If you have a very healthy blood pressure, that’s an indication of a healthy vascular system. If not, then the cholesterol may be of more concern. Check hsCRP, ferritin, homocysteine, Lp(a). You can get into others like oxLDL and fibrinogin. Depending on age, CAC may not tell you much, it is going to tell you more in older folks, or if you are younger and do not have a 0.

Sandy
Guest

Thanks for all your hard work and the podcast with Peter Attia. I follow both your work and his closely. I am currently reviewing his Straight Dope on Cholesterol and the information on your site. I need to go back and listen again to the podcast that Siabhon did with Bret Scher to complete my studies.

You did a great job of holding your own in the discussion. Peter was much more terrible and condescending to Dr Rhonda Patrick a few years ago. That one I had to turn off.

Keep up the good work. I hope you will be at the Metabolic Health Summit in Long Beach CA in January 2019.

Sandy

NJS
Guest
NJS

Hi, Dave.

That cholesterol shuttles energy through the blood as part of lipoproteins seems intuitive enough to me, I don’t dispute it. Whether its sugar, lipids, ketones, amino acids, or lactate, that these important but dangerous substances are energy sources and a necessity for life seems beyond dispute. It also obvious that the presence of these energy sources is a prerequisite for any harm that they might cause in high concentrations.

For example, we know that the body goes to some efforts to limit the concentration of sugar in the blood because high levels of glucose in the blood can cause damage to the vascular system. Likewise, in a discussion of chylomicron concentration, high enough levels can induce reduced circulation and oxygen deprivation in the limbs. High enough levels of ketones cause ketoacidosis, Ditto for lactate, it causes lactoacidosis in high concentrations. We have buffering systems of various sorts, they can be overwhelmed. You’re aware of this, so is Peter.

In your discussion of an energy model with Peter, since cholesterol is “along for the ride” as far as the lipid energy substrate goes, the debate is not over which energy substrate is valuable in some amount (they all are) but really whether the lipoprotein packaging of lipids is healthy at higher concentrations. It seems to me that cholesterol is a necessary condition for the damage that soft plaques pose. High levels of cholesterol imply more opportunity for such damage to occur, provided that other necessary conditions are present. But how high and what are other necessary conditions? That’s the devil in the details.

It wasn’t clear to me that you and Peter really disagreed on any of these points, you’re more supportive though of higher cholesterol concentrations than Peter.

Peter’s discussion of mass balance was not clearly articulated by him. All he seemed to think, was that if cholesterol recirculates, its not going somewhere else that it could. He wanted you to name what other “pool” the cholesterol was kept out of by reentering circulation instead. His other objection was mainly over the chip on his shoulder about calling cholesterol healthful, against the basic science that it is causal in arteriosclerotic disease.

In any case, I’m impressed with your approach of biohacking. I want your opinion about whether a device like the Cholestech would be useful for measuring cholesterol, or whether visits to a blood draw facility are really required for good data over months. I aspire to have the personal data about my blood cholesterol that you do. Could I use the Cholestech, or another device that you recommend, to collect information? Or do I have to go to a lab over and over?

Albany
Guest
Albany

Hi Dave,
Just adding my thoughts to the discussion:

1. As many others have commented the interview did not reflect well on Dr Attia. His attitude came over as one of contempt towards you or your work. His questions just veered the conversation away from what you were trying to say or explain. As others have said you were ever the gentleman!

2. Through your work you have uncovered a significantly large group of Low Carbers who have high LDL. (Lean Mass or otherwise). This has helped individuals to realise that they are not alone! This is a direct response from going LCHF – from glucose burners to fat burners – NOT cases due to the genetic mutations of FH.

3. Dr Attia seemed to be pressing you as to why you don’t just use the studies on FH people – I see this is problematic for several reasons. a) I would have thought one of the first principals of science would be to cut out any variables – which to me seems to be what you are trying to do in your Challenge (High LDL, High HDL, low TG’s) – why add a known genetic variable which could skew the data? – which you tried to explain to him b) What are the dietary patterns of people with FH (do we know whether they are LCHF or HCLF? and do they have high LDL, High HDL and low TG) and are they affected by their dietary pattern? c) how would LMHRs fit in to this scenario? It is possible that all the LMHR have genetic mutations that only comes to light because of their response as fat burners – but as you have rightly pointed out first you’d need to look first at studies you have asked in your challenge to see if its a problem…

4.From what I can understand there have been few studies among ‘Fat burners’ (until the Volek/Phinney study published the other day). Listening to Benjamin Bikman at Breckenridge conference he outlined that Glucose burners and Fat burners have very different insulin/glucagon responses to high protein intake, doesn’t it make sense that there may be many other responses to fat burning as opposed to glucose burning? Most dietary studies seem to be done on populations whose main source of fuel is glucose.

5. Dr Attia seemed particularly worried that as a doctor seeing High LDL = problem. Any Hyper-responder knows the consequence of this viewpoint – never mind that every other marker has improved – get the Statins started! He hasn’t appreciated that that is exactly what is so terrifying about talking to the doctor – as soon as the high LDL is seen the only solution is to put the patient on drugs! He may take a more rounded view of all markers but most doctors don’t! That doesn’t mean to say that high LDL isn’t a problem (we don’t know) but personally I’d rather have all my other markers improve and take my chances with LDL than the other way round.

6. We do know that Dr.David Unwin in the UK and Dr. Sarah Halberg (along with many others) have ‘reversed’ diabetes using LCHF. Assuming that a proportion of those are ‘hyper-responders’ it does not make sense that they are on the road to wellness if their high LDL is a problem.

7. Dr Attia seemed to either not understand or not care about your energy model – but didn’t offer any alternative explanation for being a LMHR.

I have some lipid figures going back about 10 years (I started LCHF just a few years ago when I discovered I was a hyper -responder) Do you an email address that I can send them to?

Siobhan Huggins
Admin

Hi – Dave is a tad caught up in things at the moment so I’ll make sure to put this comment on his radar for later. But, as for an email you can send it to cholesterolcode@gmail.com 🙂

Sarat V
Guest
Sarat V

Thank you for all you do to provide an alternative perspective. I am following both sides of this debate and it is really interesting. I am a software guy like you are and I am still learning a lot.

I am a bit confused on your energy model though. Assuming LMHR people are low in body fat, shouldn’t the majority of the demand be met from the chylomicron transit from the gut? Even if the demand is placed on the liver, shouldn’t the transport be VLDL (bigger boat)? If it is VLDL and the increase in LDL is just delipidated VLDL, since the half life is so low for VLDL, it would have to be a giant increase of VLDL!

Also, to me, short term changes in LDL-P is not that important. From what I understand, it is the long term exposure to high LDL-P (how high is the big question) coupled with IR and inflammation (and others) is what causes the problem. I understand that there are no studies that stratifies high HDL-P, high LDL-P and low TG. But the protective nature of HDL-P is being questioned lately. So all things being equal, high LDL-P will still cause more problems than low LDL-P. So, I can see the argument for trying to lower it.

With that it comes down to how to lower it. Stains is one way and I understand the debate about that. But if LDL-P is off the charts, it may be an option? Personally, I just limited my SF intake and it lowered my LDL significantly. Perhaps that’s an option for many?

Once again, thanks for all your knowledge sharing. You and Attia are great resources.