Cholesterol Esters: The Real "Bad" Cholesterol?

Ah cholesterol, the much vilified nutrient!  If we listen to most of the traditional nutrition and health information out there we are forced to think that cholesterol is extremely bad for us and should be avoided at all costs.  However, as many of you may know already, cholesterol is essential for human life.  It is a major component of all of our cellular membranes and is the precursor to many hormones we need (1).

Also frequently mentioned are the different types of cholesterol, the so-called “bad” cholesterol, LDL, and the “good” cholesterol HDL.  However, calling these two transport molecules cholesterol is really a misnomer, as they are complexes containing many different types of proteins, fatty acids, and only a portion of it is actual cholesterol.  These two molecules have different functions in our body, and can come in a variety of sizes.  However, labeling them “good” and “bad” cholesterol is incorrect and misleading.

So is there actually a “bad” form of cholesterol?  I have already said that cholesterol is essential for life, but there is a type of cholesterol that does appear to be bad for us.  This type of cholesterol is cholesterol esters, which is just a cholesterol molecule attached (esterified) to a fatty acid. Not all cholesterol esters are equal though, ones that are attached to polyunsaturated fatty acids (PUFAs) appear to be the most dangerous.

(2)

In a very interesting, albeit slightly old, study authors examined many different plaques that were separated into three categories: plaques in the absence of other disrupted plaques (Type A), plaques in the presence of other disrupted plaques (Type B), and disrupted plaques themselves (3).

Plaques form for many reasons, and some are more dangerous than others.  The authors of this study say that they believe their type system represents a linear progression for plaques, from Type A to Type B to Disrupted.  However, when plaques rupture they create dangerous embolisms that are able to clog even the tiniest blood vessels, and are a major cause of strokes and heart attacks (4). An embolism can be thought of like a giant boulder in the middle of a river.  It may impede the flow a bit, but if a chunk (embolus) breaks off that boulder and flows into one of the smaller tributaries of the river it may completely dam up that stream.  So learning more about the characteristics of these disrupted plaques, and the plaques that lead to them, can give us great insights into the how to treat people with plaques, and lower the risk of heart attack or stroke.

Now back to our study, the first thing these authors looked at was the lipid composition of the three types of plaques.  Here is what they found:

It is interesting that in this figure the only lipids that seem to change very much are the free cholesterol, and the cholesterol esters, meaning that these two lipids would be the most important factors that cause a ruptured plaque. However, this change in lipids is not the only factor that can cause a ruptured plaque, the authors also found that as free cholesterol and cholesterol ester concentrations increase, there is a corresponding decrease in cap thickness, and an increase in macrophage (white blood cell) accumulation. A decrease in cap thickness is highly associated with the propensity of cap to rupture, and we can think of this as like a baseball cap vs. a hard hat.  The thicker the cap (hard hat) the less likely we are to damage or rupture that plaque. 

When they took a further look at the concentration of cholesterol and cholesterol esters they found that the cholesterol esters were more abundant near the edges of a plaque. (Note on graph: FC= Free Cholesterol, EC= Esterified Cholesterol)

Not only are cholesterol esters more abundant at the edges of plaque, but also as a plaque moves from Type A to Type B to Disrupted the amount of cholesterol esters that are attached to a PUFA increase in concentration. 

These two facts are important for a couple of reasons.  First, these PUFA/cholesterol esters are highly reactive.  This reactivity with other molecules in our blood stream can damage the PUFAs, and lead to plaque rupture. The authors say this in the discussion section:

“Such damage to PUFAs, particularly at the edge of disrupted plaques, where concentrations of omega6-PUFAs are greatest, may promote connective tissue degradation and influence the prevalence of disruption at this site.”

When these PUFA attached cholesterol esters are oxidized they are known to be toxic to arterial cells and, in particular, macrophages (white blood cells) (3).  This will lead to an immune response, and inflammation, which is nearly always associated with a rupture (5).

But now the question arises, how might these cholesterol esters get into a plaque in the first place?  While some may come from errant LDL molecules, I think the majority of them come from macrophages themselves.  These macrophages may come in to help heal a plaque, but evidence shows that their morphology can be changed once at a plaque, by the composition of that plaque itself (6)!  Also, diabetics, who have an increased risk of atherosclerosis, have an increase in macrophage cholesterol ester uptake (7).  Finally, I think once inside a macrophage, constant energy excess helps to trap the cholesterol esters inside the macrophage.  This study indicated that a cholesterol ester cycle exists within isolate macrophage, and that it is dependent upon ATP (8).  So if we are at a constant energy excess, like with a typical SAD dieter, and especially in diabetics, we will continue to build up cholesterol esters in our macrophages.  It is important note though, that that study was done in isolated mice macrohpages, and was relatively old, but constant energy excess can be seen as a cause of accelerated atherosclerosis in many other ways, including increased reactive oxygen species and AGE accumulation.

We have seen that cholesterol esters are highly correlated to disrupted plaques, and also in Type B plaques that are next in line to rupture.  Also, we know that these types of molecules are highly reactive, and when concentrated near the edge of plaque, like in Type B and disrupted plaques, greatly increase the chance that the plaque will rupture.   Also, macrophages may be the primary driver of cholesterol esters into plaques, and this can be seen by the increase in cholesterol ester concentration in diabetic macrophages.  Also, constant energy excess can have disastrous effects on our bodies, and can trap cholesterol esters inside macrophages.   This ability to damage a plaque and cause a rupture is why I would call cholesterol esters the real “bad” cholesterol.