LDL Particles

1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
2. The pool of cholesterol in our body is essential for life.  No cholesterol = no life.
3. Cholesterol exists in 2 forms – unesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control.  I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion.  Anyone who tells you different is, at best, ignorant of this topic.  At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up.  To see an important reference on this topic, please look here.

HOPEFULLY VISITORS HERE ARE DISCERNING - IF SO THEY MIGHT LIKE TO read this and this

1. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
2. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
3. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
4. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells.  The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles.
5. Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the “gut”).
6. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
7. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids.
8. The measurement of cholesterol has undergone a dramatic evolution over the past 70 years with technology at the heart of the advance.
9. Currently, most people in the United States (and the world for that matter) undergo a “standard” lipid panel, which only directly measures TC, TG, andHDL-C.  LDL-C is measured or most often estimated.
10. More advanced cholesterol measuring tests do exist to directly measure LDL-C (though none are standardized), along with the cholesterol content of other lipoproteins (e.g., VLDL, IDL) or lipoprotein subparticles.
11. The most frequently used and guideline-recommended test that can count the number of LDL particles is either apolipoprotein B or LDL-P NMR, which is part of the NMR LipoProfile.  NMR can also measure the size of LDL and other lipoprotein particles, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels.
12. The progression from a completely normal artery to a “clogged” or atherosclerotic one follows a very clear path: an apoB containing particle gets past the endothelial layer into the subendothelial space, the particle and its cholesterol content is retained, immune cells arrive, an inflammatory response ensues “fixing” the apoB containing particles in place AND making more space for more of them.
13. While inflammation plays a key role in this process, it’s the penetration of the endothelium and retention within the endothelium that drive the process.
14. The most common apoB containing lipoprotein in this process is certainly the LDL particle. However, Lp(a) and apoB containing lipoproteins play a role also, especially in the insulin resistant person.
15. If you want to stop atherosclerosis, you must lower the LDL particle number.

Concept #7 – Does the size of an LDL particle matter?

There are few, if any, topics in lipidology that generate more confusion and argument that this one.  I’ve been leading up to it all month, so I think the time is here to address this issue head on.  I’ve read many papers and seen many lectures on this topic, but the one that stole my heart was a lecture given by Jim Otvos at the ADA 66th Scientific Sessions in Washington, DC.   Some of the figures I am using in this post are taken directly or modified from his talk or subsequent discussions.

At the outset of this discussion I want to point out two clinical scenarios to keep in mind:

1. The most lethal lipoprotein disorder is familial hypercholesterolemia, which I have discussed in previous posts.  Such patients all have large LDL particles, but most of these patients die in childhood or early adulthood if not treated with medications to reduce particle number.
2. Conversely, diabetic patients and other patients with advanced metabolic syndrome have small LDL particles, yet often live well into their 50s and 60s before succumbing to atherosclerotic diseases.

The common denominator is that both sets of patients in (1) and (2) have high LDL-P.  What I’m going to attempt to show you today is that once adjusted for particle number, particle size has no statistically significant relationship to cardiovascular risk.  But first, some geometry.

Read on for the full article