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.
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.
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.
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).