Before you proceed, I suggest reading this article which is a lead-in to the current article. However, if you prefer not, then it’s sufficient to know this:
The oversimplification of cardiovascular disease risk assessment—in which LDL-cholesterol is often the primary diagnostic, prognostic, and therapeutic target—leads to effective treatment of some people, but the ineffective treatment of others.
My goal in this article is for us to gain a more complete understanding of cholesterol for the purpose of taking an individualized approach to cardiovascular disease risk assessment and prevention.
This article is the first of several that will attempt to explain the factors that go into an individualized cardiovascular risk assessment.
In this article, we’ll focus on cholesterol, and specifically, the following questions.
- What is cholesterol?
- What is the function of cholesterol?
- Where does it come from?
- How does it get into and out of your body?
- How does cholesterol move around in the blood?
- Why do people say that LDL-cholesterol is bad?
- Is it true that higher LDL-cholesterol is bad and lower is good?
What is cholesterol?
Cholesterol is a lipid — a molecule that is insoluble in water and includes oils, waxes, and steroids.
An example of a lipid that you’ve no doubt consumed on countless occasions is oleic acid, which makes up the majority of the molecules in a bottle of olive oil. Oleic acid is a monounsaturated fatty acid, which makes it a lipid.
Here is oleic acid:
Another example is butter, which is predominantly made of a fatty acid called palmitic acid. Here is palmitic acid:
Cholesterol is also a lipid, but it’s not a fatty acid. Here is its molecular structure:
What is the function of cholesterol?
Cholesterol is an important molecule that is present in every single cell of the body. On average, it composes thirty percent of animal cell membranes and allows membranes to be flexible and fluid so that they can move without breaking.
Cholesterol is also the structure from which steroid hormones are synthesized. Cortisol, testosterone, and estradiol are a few examples of steroid hormones that start out as cholesterol molecules.
Where does cholesterol come from?
Nearly every cell in our bodies can synthesize cholesterol within its own boundaries. This means that most cells do not need to obtain cholesterol from the blood stream.
In addition to synthesizing cholesterol within our cells, we can also absorb cholesterol from the food we eat. Humans aren’t the only animals that can synthesize cholesterol. In fact, all animals synthesize cholesterol. When we eat animals, we’re necessarily eating the cholesterol found within their cells.
Most of the cholesterol in our bodies is found within cell membranes. Only a tiny percentage of total body cholesterol is found in the blood stream at any given time.
So, we can synthesize cholesterol, but we can also eat cholesterol that’s been synthesized by other animals.
Of note, plants do not contain cholesterol. Instead, they contain similar molecules called phytosterols.
By and large, most people do not absorb very much of the dietary cholesterol that they eat, and we absorb even less of the phytosterol that we eat. Most dietary cholesterol, usually around seventy-five percent, will be flushed down the toilet along with nearly all phytosterols.
So, cholesterol can be both absorbed and synthesized. Excess dietary cholesterol and plant sterols can be excreted in feces.
How does cholesterol get into and out of our bodies?
When we eat, food is broken down in the stomach and eventually reaches the small bowel. It’s at the end of the small bowel, the ileum, that most cholesterol absorption occurs.
In the ileum, cells that line the bowel wall called enterocytes are responsible for absorbing nutrients including fat and some cholesterol.
In a prior issue, I wrote about a remarkable surgeon named Dr. Buchwald. In the 1960s, he pioneered and performed a surgical procedure called “partial ileal bypass” in order to prevent absorption of cholesterol in the ileum. While drastic by today’s standards, the procedure was successful in some subjects in reducing serum cholesterol levels.
Once cholesterol crosses the membrane into the enterocyte, efflux pumps called the ABCG5 and G8 sterol transporters can get rid of extra cholesterol by pumping it back into the bowel where, hopefully, it will undergo a quick courtesy flush. These pumps also ensure that dietary plant sterols are pumped back into the bowel so that we don’t absorb them.
The pumps aren’t perfect, and so we do absorb a very small amount of plant sterols. In some people, these pumps don’t work very well at all. These people absorb more dietary cholesterol and plant sterols as well.
In a rare condition called beta-sitosterolemia or phytosterolemia, patients can absorb so much dietary plant sterol that it actually causes a clinical picture similar to people with severely elevated cholesterol. These patients can suffer from premature heart attacks due to the hyper-absorption of plant sterols which eventually deposit in artery walls and cause coronary artery disease.
It’s worth noting that there is significant inter-individual variation in the absorption of dietary cholesterol and the compensation thereof.
Not only is there inter-individual variation, there is intra-individual variation. This means that if we measure our cholesterol absorption today, it might not be quite the same in a year from now if our diet differs or if we’re on certain medications. For instance, some people who take statins (medications that decrease cholesterol synthesis), may eventually absorb more cholesterol from their diet.
How does cholesterol move around in the blood?
Once cholesterol gets absorbed by the cells lining the bowel wall, it’s packaged into lipoproteins called chylomicrons.
I know this next part may seem complex, but it’s worth learning because it’s essential for everything that follows.
Almost all cholesterol travels in the blood stream as a passenger in ovoid or spherical vehicles called lipoproteins.
Source: Lipid Homeostasis and Transport
As the name suggests, lipoproteins are composed of lipids (lipo-) and proteins.
The two main lipids carried by lipoproteins are fatty acids, and triglycerides both of which you can think of as fuel or gasoline that will get delivered to cells either for storage or to burn for energy.
The lipoproteins also carry cholesterol.
The proteins of the lipoprotein are responsible for determining the size, shape, and function of the lipoprotein. These proteins are called apoproteins.
Here is a non-exhaustive list of apoproteins: A, a, B48, B100, CI, CII, CIII, and E.
Each LDL particle has a single Apo B100 protein. VLDL particles are similar, but they also have Apo E and may have one or more Apo C proteins as well. The point is, different lipoproteins have different apoproteins and these apoproteins determine the particle’s form and function.
James Bond drives an Aston Martin. He’s got a few guns in the back and some passports in the glove box. Bond decides where the car goes and what he does.
You can think of a lipoprotein as a vehicle – the Aston Martin. The type of vehicle, its function, cargo, origin, and destination are decided by a driver, the apoprotein – Bond. The cargo is usually some combination of fatty acids, triglycerides, and cholesterol – guns, passports, etc.
The simplest lipoprotein may be the chylomicron. The chylomicron’s apoprotein is the B48 apoprotein.
The chylomicron’s origin is the bowel. Its function is to absorb dietary fat, cholesterol, and fat soluble vitamins (A,D,E,K) and bring them to the liver.
Once these nutrients get to the liver, the chylomicron breaks down and the liver repackages these nutrients into a new lipoprotein called a VLDL (very low density lipoprotein). The VLDL delivers fat (fuel), vitamins, and cholesterol to different cells within the body. As it makes these deliveries, it shrinks in size and eventually becomes the infamous LDL particle.
LDL, low-density lipoprotein is a particle—a vehicle—not a type of cholesterol.
LDL is just one vehicle in which cholesterol can travel.
Why do people say that LDL-cholesterol is bad?
In addition to the cholesterol found in LDL (low-density lipoproteins), we can also find cholesterol in every other lipoprotein – VLDL (very-low), IDL (intermediate), HDL (high), chylomicrons, and the cell membrane of every cell.
Why is the cholesterol in LDL particles worse than the cholesterol anywhere else?
Inherently, it isn’t.
It’s just that, by their nature, LDL particles are in circulation the longest.
The other lipoproteins are either short-lived (chylomicrons), responsible for reverse cholesterol transport (HDL), or they’re precursors to LDL (VLDL and IDL).
This leaves LDL as the longest-lived particle which contains more cholesterol content by weight than the other particles. It’s the end of the metabolic pathway. LDL can’t evolve into another particle; it can’t transfer its cholesterol to another particle; and it can only be removed from the blood stream in two ways.
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LDL particles can be taken out of circulation by any cell that has an LDL receptor. Under normal circumstances, roughly two-thirds of circulating LDL is removed by LDL receptors on the liver. Once LDL is taken up by the liver, its cholesterol can either be repackaged and sent back into the blood, or it can be excreted into the bile where some of it can eventually become part of our stool. By this process, we can clear LDL from the blood stream and rid our bodies of excess cholesterol.
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If the process whereby LDL particles return to the liver is defective or disrupted, LDL particles will instead be cleared by other receptors on other cells. Cholesterol cleared by these alternative methods might eventually find its way back to the liver via the reverse cholesterol transport system. But, sometimes, cholesterol cleared in this manner will instead find its way into surprising and undesirable locations.
For instance, in patients with familial hypercholesterolemia who lack the gene for the LDL receptor, these patients cannot clear LDL particles from the blood stream via the normal method.
In these patients, LDL and its cholesterol find their way into the cornea, the skin around the eyes, the tendons of hands and feet, and into the walls of the arteries.
Even in people with normal LDL receptors, conditions like diabetes, obesity, and the metabolic syndrome can lead to dysregulation of lipoprotein metabolism. The system becomes overwhelmed. Traffic jams and accidents occur. LDL particles can’t get off the highway into the liver. Some are damaged when they crash into sugar molecules or become oxidized. These particles end up broken down on the roadside. Some are picked up by tow trucks and get taken to the junkyard.
Imagine if these proverbial wrecked cars weren’t removed from the highway. Eventually they’re going to narrow the available roadway. This is a very very rough, almost inexcusably over-simplified analogy for coronary artery disease, but I think it illustrates the point. If we can’t clear LDL particles by the normal method, they may end up in places we don’t want.
In the case of coronary atherosclerosis, the process is more complex, but the end result can be disastrous.
When LDL particles are retained within the artery wall, a sickening process of runaway inflammation can occur. Eventually, a pimple-like plaque can form. If this plaque ruptures into the artery’s lumen, blood clots form. If the clot completely obstructs the vessel, and the vessel is a major artery that supplies blood flow to our heart muscle (myocardium), we lose blood flow to a section of our heart. Without blood, the myocardium has no oxygen, and it quickly dies. Tissue death is called "infarction," hence the medical term for a heart attack: myocardial infarction.
It’s for this reason that the cholesterol from LDL particles gets such a bad rap.
Is it true that higher LDL-cholesterol is bad and lower is good?
LDL-cholesterol numbers are a poor predictor of the risk of coronary artery disease on an individual basis.
Let me illustrate the point.
I mentioned earlier that some patients have genetic mutations that cause them to lack the LDL receptor that is responsible for removing LDL particles from the blood stream.
The most severe version of this mutation (homozygous FH) may only occur in roughly one out of every 500,000 people, but it can teach us something very important about the way that LDL and cholesterol relate to the risk of coronary artery disease.
People with FH, in particular those who lack the gene for the LDL receptor, have LDL-cholesterol levels that are two to six times the normal level and are thus given the clinical diagnosis of familial hypercholesterolemia (FH).
Let’s look at some actual numbers.
My plasma LDL-cholesterol concentration is right around 100 mg/dl.
An FH patient has levels from 200 mg/dl to 700 mg/dl.
Consider this case of a woman with familial hypercholesterolemia whose LDL cholesterol was five times the normal level. She developed severe coronary artery disease and suffered a heart attack at the age of eighteen.
I know what you’re thinking. This is a fringe case, but it serves to illustrate an important point.
A person who is unable to clear LDL-cholesterol from the blood stream is at very high risk of developing high levels of LDL-cholesterol in their blood. Under these circumstances, people can develop premature atherosclerotic cardiovascular disease.
LDL-cholesterol is an essential component of this process. So it follows that lowering its level in the blood stream might be an effective way of delaying the onset of atherosclerosis, and therefore may prolong the lifespan and health span of many people.
But, does everyone need to have lower LDL-cholesterol, or are some people going to be just fine despite high levels?
How can LDL-cholesterol be decreased?
Why is it elevated in the first place?
In my next article, I will discuss LDL-cholesterol in more detail. We’ll discuss another interesting condition, hypobetalipoproteinemia, a genetic condition in which people have extremely low levels of LDL-cholesterol. We’ll look at different ways to measure and think about LDL-cholesterol, and different ways to modify its level in our blood.
Eventually, this knowledge will help us build towards an understanding of personalized cardiovascular risk assessment and mitigation with the ultimate goal of delaying or preventing atherosclerotic cardiovascular disease.
— Steve