The Secret Cholesterol Theory
Completely accidentally I bumped into an article about osteocalcin, and it turned out to be something pretty important. My research about the fight-or-flight mechanism, which is associated with migraine, led me to this article. Those of you who follow me know that my research is in migraines and not with cholesterol. My understanding had been that when humans encounter danger or stress they respond with a “fight or flight” which is initiated by the central nervous system and stress hormones, such as adrenaline(1). According to this article this is not the case.
The initiation is performed by osteocalcin (defined and discusses below.) What’s osteocalcin’s connection to cholesterol? Actually, nothing directly but plenty indirectly, through calcium. Atheroma is calcified (calcium filled) cholesterol forming atherosclerosis in all the wrong places, and a very negative condition. The sequence leading to it is as follows:
Stress => Osteocalcin = T2D, Atheroma, Calcium, CVD
Indeed! Who would have thought? As you know, there is a war going on about cholesterol and its role in cardiovascular disease, atherosclerosis, and death. The main, traditionalist camp is convinced that the cause of atherosclerosis is high LDL.
An opposing camp, rapidly gaining more and more adherents, suggests that atherosclerosis is caused by inflammatory processes, which may be the consequence of eating industrially produced PUFA oils–vegetable and seed oils; and/or consuming too much sugar—sugar is inflammatory and is associated with type 2 diabetes (T2D) and obesity. This camp also posits that there is no cardiovascular disease without T2D, the two are associated.
The predominant theory of the inflammatory concept suggests that the problem starts in the arteries where the artery walls are crossed by LDL particles—usually they mention small dense LDL particles. They are small and dense because they are oxidized and are not functional. These then lodge in the wall of the arteries, and after a host of immune attacks by macrophages, calcium also moves in from the blood and deposits, making the atheroma hard. This then may burst one day as the calcium gets loose (not much explanation on how and why that happens). According to this theory, the LDL particles magically cross like ghosts though the endothelium (a thin single-layer cell surface separating the lumen, which is where the blood flows from the smooth muscles of the artery) without any damage to the endothelium, and after they reached the outer wall, where the smooth muscle is, then settle…
This is a great theory up until this last part, and that is because examining such atheroma under microscope reveals that there are torn smooth muscle pieces in the atheroma. If so, the crossing of the LDL must have happened from the other side, the smooth muscle and not the lumen side through the endothelium.
Another inflammatory theory suggests that LDL crosses from the outside of the arteries—by Vladimir M. Subbotin in his awesome article here. His theory differs from the LDL particles crossing via the lumen, noting that the concentration of the atheroma is actually not close to the lumen but is deep inside on the bottom of the artery wall, closer to the tunica intima, the side of the artery facing the body. So, if the atheroma has torn smooth muscle cells in it, then clearly the entry is the region of the tear… right? Well that’s just me thinking too logically…
The fourth theory is the one that just came to my attention. Most of the articles on this theory are new. This discusses osteocalcin as the reason for calcification of the atheroma, independent of where the LDL managed to cross into the artery wall. This is the only theory it seems that ignores LDL’s presence and focuses instead on calcification.
Oddity
Before we continue, I must also mention that there is at least one tribe living today, Tsimane, that has high levels of atherosclerosis without CVD (2). Very few members had CAC scores over zero in this tribe, though many had high levels of inflammatory marker c-reactive protein, which was way over 3, the maximum normal cutoff in Western societies. This would indicate that the factor of importance really is the calcification of the atheroma and not the atheroma itself.
What is Osteocalcin?
Osteocalcin “is a non-collagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein in chick bone. Because it has gla domains, its synthesis is vitamin K dependent.” (wikipedia)
The Role of Osteocalcin
Few argue that Cardiovascular Disease (CVD) is a metabolic disease and that it is somehow connected to glucose and insulin mismanagement of the body. The modern CVD theories agree and incorporate metabolic disease, many of them even define CVD as a metabolic disease. However, the development of the connection between metabolic disease and CVD is less understood and seldom discussed.
Crucially, osteocalcin is associated with glucose management: “One of the functions regulated by bone through osteocalcin, an osteoblast specific hormone, is glucose homeostasis” (here). Studying up more about osteocalcin, we can learn that “bone is an endocrine organ regulating a growing number of physiological processes“(3)
As most of us who are students of heart disease, T2D, obesity, or other forms of metabolic diseases know, calcium is key marker of atherosclerosis. It is said that calcium appears at the site of the budding deposit that turns into atheroma, which provides support to the atheroma so it has less chance of bursting(4). While we may disagree about which side the LDL enters the artery to cause its trouble, we may most certainly agree that it is causing trouble most when it gets calcified.
When does osteocalcin enter the picture? Glad you asked. It comes with stress! And I think this is the real culprit and not T2D. That’s because stress initiates hormones that are responsible for generating glucose, initiating insulin resistance, and modifying glucose homeostasis. And what hormone may do all this? Osteocalcin.
Conclusion
I pride myself in finding holes in many arguments. I may not be always correct, but I strongly believe holes definitely exist in the current explanations of CVD. Could it be that the real cause of CVD is stress? See some article here or here(5) or here or here.
My suspicion is that we have been chasing the wrong suspect. Food certainly has much to do with CVD because eating the wrong food can cause stress—sugar is well understood to trigger stress and stress is well-understood to cause elevated blood sugar. And chronic elevated blood sugar leads to T2D which then leads to inflammatory processes. But stress on its own is also causing the release of osteocalcin, which then is just very happy to stick to wherever it can, causing calcification of atheroma. This is a new and intriguing theory, deserving your attention.
Comments are welcome, as always, and are moderated for appropriateness.
Angela
Sources:
1 Berger, J. M. et al. Mediation of the Acute Stress Response by the Skeleton. Cell Metabolism, doi:10.1016/j.cmet.2019.08.012.
2 Kaplan, H. et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet 389, 1730-1739, doi:10.1016/S0140-6736(17)30752-3 (2017).
3 Wei, J. & Karsenty, G. An Overview of the Metabolic Functions of Osteocalcin. Current Osteoporosis Reports 13, 180-185, doi:10.1007/s11914-015-0267-y (2015).
4 Aimilios, K. et al. Basic Mechanisms in Atherosclerosis: The Role of Calcium. Medicinal Chemistry 12, 103-113, doi:http://dx.doi.org/10.2174/1573406411666150928111446 (2016).
5 Choi, B.-h. et al. Coronary artery calcification is associated with high serum concentration of undercarboxylated osteocalcin in asymptomatic Korean men. Clinical Endocrinology 83, 320-326, doi:10.1111/cen.12792 (2015).
Fascinating explanation of the ‘How & Why’. I’d love think you’ve got it.
Thank you !
There is a difference between how we react to happy stress…and horrible stress.
The former is… like taking off on my First Solo Flight, and the thought was “This is going to be FUN”
Horrible stress is standing up in front of an audience and realizing a zip is undone, and for the next 40 minutes…
I’m also convinced that *mis-handled* stress – or ‘strain’ as Dr Kendrick calls it, is pivotal to CVD.
In my case, CABG x5 very much so. Not only but also, my life history ticks too many boxes for Good cardiac health… eg, bullied at middle-High school, parents split when young, no siblings or extended family, too many shifts of residence to keep friends and inclination towards depressive episodes Plus my working life was rotating shifts, in a job I had no great passion for.
Don’t forget the T2 Diabetes / obesity /fitness deficiency…
Then, 12 months of constant stress, personal, financial and “legal”… resulting in loss of weight control / A1c regulation and self-image in a massive unending depression…. It’s no wonder – with hindsight – that my heart did it’s best to end it all for me !
Proverbs Ch 17 verse 22 says it all – and notice the inclusion of…. bones !
“A joyful heart is good medicine, But a broken spirit dries up the bones.”
Blue Zones the world over, have close personal & social support as the Common Factor, with ‘wholesome’ diets coming in after. – They vary enough to put them in second place.
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Glad you are coming around. Most everything broken can be repaired–though they may never look or behave like new, they will work just fine. 😉 Enjoy your new life and recovery!
The “Blue Zone” is all fake… none of what they labeled as “Blue Zone” fits the mold today and some never fit the mold in the past (Like in Japan or even in Loma Linda, which is a stone throw away from where I live, and where I almost ended up doing some research. Including that even mustard is forbidden for its “excitatory effects”, it is a horrible vegan-special diet with more restrictions than a standard vegan. What keeps people live longer (or used to.. not anymore) is the strong social-community-like nature of Loma Linda.
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Yesterday night I asked you about a new drug for T2D called Rybelsus which was recently approved by the FDA. But my message isn’t visible anymore. So I sent this one.
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Sorry, I have not yet been online since yesterday evening. Trying to finish writing a book, so I turned off all my online toys. 😉 I read both emails (I get an email when I get a message posted) just now.
It is a GLP-1 drug, glucagon-like peptide 1, receptor agonist, meaning they increase glucagon-like peptide. There is a pretty bad safety record for these drugs when injected–this is the first one that is by a different mechanism; not sure what it is. Whatever it is, it is making T2D worse by forcefully reducing the symptoms, which is high blood glucose… it is like placing your broken arm on a rack and constantly hit it with a bat, while you are drugged to not feel the pain.
These drugs are all misguided in that they only remove the symptom but to do so, they actually make the condition worse.
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Apart from the “money thing”, why the heck is stuff like this brought to the consumer? Are the “experts” thát stupid?
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Money talks. No one cares about curing people. Keeping them dependent on drugs is key.. right? So smart people because they go home with pockets full of money.
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Like I said b4, this also confirms my distrust in whatever authority is sitting in the drivers seat. Time for those people to rot in hell, I’d say.
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I couldn’t agree with you more!
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Rybelsus for T2D is FDA approved now. Your take on this?
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Re: “But stress on its own is also causing the release of osteocalcin……..” Negative as well as positive stress?
Talking about negative stress. I’m one of those who, for as long as I can remember, is living with it on a daily basis. Seems to me it’s based on my from childhood on developed and now ingrained anger with moron authorities hypocritically pushing their hidden agendas, as well as with their opportunistic lackeys, ignorant supporters, and indifferent followers. And yet………even after multiple visits to cardiologists triggered by a shitload of times I had all the classical symptoms of having a heart-disease/attack, I always came out clean. In my twenties a professor once told me: “Mister Michel, we can go on and on, but there’s nothing wrong with your heart.” Being now in my seventies, I’m told the same thing 😛
Note: As a long time online friend I feel I also have to tell you, that since last month my stress level has increased exponentially. Why is that? Because Lucitta died. I know you’re extremely busy, but if you want to know more about the latter, then, because I know the 2 of you are friends there, go to her FB page. Or mine for that matter. On both you can find several entries regarding her death.
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OMG Roald, I am so sorry! I have been too busy and didn’t visit her FB page. My deepest condolences to you and Vanessa! ❤ I have known that she was ill and all I can say is that at last she is in no pain. ❤ That won't heal your sorrow but at least her suffering is over. She was a wonderful person from the few times we exchanged words. She will be missed. ❤
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Thx. It’s extremely hard to accept she’s gone. Trying now to find out what to do with the rest of my time. Currently I’m devouring a cocktail consisting grief, desperation, anger, hopelessness, aggression, and other foul ingredients.
Still, what’s your take on my stress story?
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I think what you are going through is totally normal and I would not call it an unnatural stress story. I would think that you need to mourn the best way you can, just be sure you do, because otherwise the pain won’t leave. I have not lost anyone that close to me in my life, so I cannot even imagine what you are going through now. I am not sure what I would do so I cannot even recommend anything other than change your lifestyle from what you had before. Change what you do and when you do it so that you are not reminded of little things you always did together. That’s what I would do. ❤
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I see your point. It makes sense too. Given the way we lived together, also the real estate we own, all the stuff coming with all that, it will take a lot of time to organize/change same. And then there’s this too……. I don’t want to let her go 🎎
The other thing I was asking your opinion about was related to that osteocalcin thingy, as stress didn’t do to me what was suggested by the article you shared.
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You have no choice but to let her go because you have a future to think of. How you feel now is transient–regardless how long it lasts. ❤
In terms of stress and how it affected you. Not sure I understand what you mean: do you mean the fight-or-flight?? I think that there are several types of stresses and it is not clear that fight-or-flight and/or osteocalcin is part of each type. I don't suppose that the stress released by skydiving for the first time is the same experience as getting a first job, or having a loved one die, or getting your first new car. Each of these is a stress but each is very different in what they activate, plus they differ among people.
For example, when I was teaching in the university, I often had classes of several hundred in huge lecture halls and sometimes those lecture halls were filled with faculty to whom I lectured. The stress I felt totally fit me–I got a "high" from that stress. Yet pull a few typical people off the street and place them into that situation and watch some faint from stress. Feeling happy and looking forward to public speaking would have a very different stress response than feeling scared of public speaking. Same activity, different stress response.
So I think there is a lot more to this that none of the articles I discussed covered. Plus, in some situations, fight-or-flight exists without us actually being conscious of it. Migraine is very typical for that. I discuss this in my book. The first step in migraine is a fight-or-flight but few of us actually feel the fight-or-flight.
However, we may have its symptoms only we call these something else, even though they are all part of fight-or-flight: a sudden urge of a bowel movement out of regular timing and much bigger, a sudden urge to frequent urination, a bit faster heart rate than usual, being a bit out of breath perhaps, maybe a slight dizziness, a bit of nausea and maybe even vomiting, and many more. These are all symptoms of fight-or-flight without feeling anxiety. So you may have had the fight-or-flight without discovering it.
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Yes, I too can flourish under positive stress. That’s why I asked: “Negative as well as positive stress?”
Re: “Could it be that the real cause of CVD is stress?” & “…..osteocalcin, which then is just very happy to stick to wherever it can, causing calcification of atheroma.” Seems (well….um…..up till now) not to have happened in my case 😛
Re: “fight-or-flight”. There’s also “freeze” ⛄️
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I suppose CVD takes some time to develop and probably there are genetic factors mixed in there based on our reactions.
Yes, I am sure it is extremely hard to accept that she is gone. I don’t know what to recommend since I have not had the experience–I don’t have the right to recommend. Your body and mind will tell you how to advance. ❤
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Oh I’m so sorry! i wondered where you’d gone.
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BRILLIANT piece, thank you!!
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I’ve heard the same line where stress is the key trigger of CVD from Dr. Malcolm Kendrick. Thanks for another great post!
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Yes and in a recent post one of the replies was from someone looking at calcium metabolism.
I spent most of my life suffering from reactive hypoglycemia. A lack of Phase 1 insulin means my glucose spikes on eating carbs, then the Phase 2 turns up and knocks it back down again but fails to shut off and the rapid drop in glucose releases counterregulatory hormones including cortisol, epinephrine and norepinephrine which explains my mood symptoms and reacting as if |I was under stress when I wasn’t. All gone thanks to a low carb/keto diet. Maybe one more mechanism where diabetes is a cardiovascular risk.
I came across osteocalcin before in the context of diabetes also. \now to read these papers . . .
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Many of the migraineurs I work with have reactive hypoglycemia. To recover from that, I place them on the carnivore diet. It seems to work very well for most–not all so far.
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It’s amazing what you can see in retrospect! I used to get migraines, but they were comparatively mild and uncommon, so I lived with them, On the other hand I never had “normal” headaches, ie. without visual and sometimes aural disturbances.
Now I realise they occurred in the afternoon or evening a few hours after eating too many carbs. Yet another symptom that went away once I nailed my blood glucose.
Ok I’ve read your references, fascinating stuff! I only read one of them before. This one
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213520/
looks to have some good links too.
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Thanks! Great that your migraines responded so well. For most migraineurs–particularly those on dozens of brain numbing drugs–it is not that easy.
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