What is cholesterol?
A full discussion of lipidology is beyond the scope of this educational piece. Here I will provide a basic roadmap to explain what cholesterol is, how it is transported in the body, and how it causes vascular disease.
Cholesterol is essential for life. It stabilizes the cell membrane and gives it fluidity. Cholesterol is also used to produce other molecules; for example, it is delivered to steroid-producing tissues such as adrenal glands and testes where it is converted to hormones such as cortisol and testosterone, respectively. Cholesterol is a constituent of bile, which is used for digestion. Every cell in the body has the ability to make its own cholesterol.
However, cholesterol has a central role in the pathogenesis of vascular disease, which develops quietly over decades, usually causing no symptoms, until a catastrophic event such as myocardial infarction (heart attack) or cerebral infarction (stroke) occurs. People often tell me “But I feel fine” when I advise them that they are at high risk for these events.
What is atherosclerosis?
Atherosclerosis is a chronic, inflammatory process which damages the arteries that provide oxygen and fuel to the muscle and organs. When I was in medical school, I was able to hold diseased, calcified arteries in my hand. It left an impression. Sclerosis means hardening. Over time, cholesterol plaques mature and calcify, turning a once soft and pliable artery into a hard and calcified vessel. The diseased artery produces less nitric oxide, an important chemical that relaxes and widens the artery, reduces blood clotting, and reduces migration of white blood cells into the artery lining.
Atherosclerosis is a common disease in the developed world because our current way of living, which includes a sedentary lifestyle and a diet high in calories, carbohydrates, processed food, and saturated fat, has promoted hypertension, obesity, insulin resistance, type 2 diabetes, and chronic inflammation, all of which damage the artery. Our blood cholesterol levels are often far above our natural physiological requirement. And, as you will see below, the metabolic stress imposed by our dietary habits has changed the distribution of the lipoproteins that transport the cholesterol in our blood. Therefore, in the modern world, cholesterol has become both friend and foe.
Many people use the term “high cholesterol” to describe how cholesterol causes vascular disease. Your body’s system for producing, transporting, and excreting cholesterol is very complicated; there are many places in the system where something could go wrong. Since the issue is more nuanced than “high cholesterol,” I prefer to call it dyslipidemia (“dys” meaning something has gone wrong).
Triglycerides are fat molecules used as fuel for skeletal muscle and energy storage within adipose tissue. Triglycerides do not cause atherosclerosis. I often hear scientists or physicians talking about “fat” in the artery causing atherosclerosis. I believe that they are trying to simplify the explanation to listeners. Unfortunately, this leads to a misunderstanding of the process of vascular disease.
How is cholesterol transported in the body?
I will introduce the subject of lipid transport. Lipids are oily organic macromolecules which cannot dissolve in water. Examples include:
Cholesterol, which is necessary for cell membrane structure and fluidity, in addition to being a molecule that is transformed into various steroid hormones
Phospholipids, which are an integral part of the cell wall
Triglycerides, which are a source of fuel for muscle and adipose tissue
Since lipids cannot dissolve in blood (blood is mainly water), your body uses water-soluble lipoproteins (also called lipoprotein particles) to transport lipids within the bloodstream. Common lipoproteins include VLDL, LDL, Lp(a), and HDL.
As mentioned above, every cell in the body can produce its own cholesterol. However, your body needs to maintain a balance between producing enough cholesterol for life but also removing cholesterol from the body when there is excess. If we do not have enough cholesterol; our body cannot function properly. If we have too much cholesterol within the cells, it may crystallize within the cell, killing it, or the cholesterol may deposit into the artery wall to cause dementia, coronary artery disease, erectile dysfunction, and so on. This process of balance is called homeostasis:
At any given time in your body:
- Cholesterol is being produced within all the cells of your body, including the liver
- Cholesterol is being sent from your liver into the bloodstream within lipoproteins
- Lipoproteins such as HDL and LDL are returning to the liver from the bloodstream where components are recycled
- The liver is secreting cholesterol (within bile) into your digestive tract, where it may pass out of you or be reabsorbed from the small intestine
- The small intestine is absorbing cholesterol via the Neimann-Pick C1 protein and passing it into the blood stream
- The small intestine is excreting cholesterol via the ABC G5/G8 pump, where it may pass out of you
Your liver uses water soluble particles called lipoproteins to deliver lipids to their target tissues. Your liver loads cholesterol into a lipoprotein called VLDL, causing it to assume a spherical shape, which increases its volume and allows more phospholipids and triglycerides to be packed inside. The liver then passes VLDL into the bloodstream. where it stops at muscle and adipose tissue to deposit triglycerides. VLDL, now deprived of its fat, turns into an LDL particle. Hopefully, the LDL particle will return to the liver by binding to the LDL receptor, where it is then brought into the liver for recycling. The cholesterol returned to the liver by the LDL particle can be secreted into the intestine within bile or passed into the bloodstream once again within VLDL.
HDL is a lipoprotein that can deliver cholesterol to steroid-producing tissues to make hormones such as cortisol, in time of excess need, such as during high stress. However, HDL has another important function. It removes the cholesterol that has been deposited into the artery lining, or from tissues that have overproduced cholesterol, and returns it to the liver. HDL can flow into and out of the artery lining.
Current theory about Lp(a) suggests that it is a scavenger of oxidized phospholipids (which can cause artery disease). After scavenging oxidized phospholipids, Lp(a) binds to the LDL receptor on the liver and is removed from the circulation. The problem is that Lp(a) does not readily bind to the LDL receptor and tends to remain elevated within the bloodstream; this increases the concentration of Lp(a) within the blood, increasing the chances of Lp(a) depositing into the artery lining.
I want to discuss the process of the effect of insulin resistance on atherosclerosis. Insulin resistance (more often observed in people with obesity and overconsumption of calories and carbohydrates), also known as metabolic syndrome, is a common condition in developed countries. This causes a redistribution of cholesterol within lipoproteins. Insulin resistance induces an enzyme called CETP to transfer cholesterol from LDL and HDL back to VLDL (LDL-cholesterol and HDL-cholesterol drop, and VLDL-cholesterol increases). The LDL and HDL particles shrink. The LDL particles become smaller, denser and more numerous, and the HDL particles become smaller and are lost from the body via the urine.
The LDL particle, now much smaller, has a difficult time returning to the liver. The liver receptor for the LDL particle has a hard time recognizing and binding the smaller LDL particle. Therefore, LDL particle concentration within the blood increases, and (through a process called gradient pressure) more of the LDL particles deposit into the artery lining. An LDL particle is more easily able to enter a lining that has been damaged by hypertension, type 2 diabetes, and cigarette smoking. When the cholesterol within the LDL particle becomes oxidized by free radicals, white blood cells see the oxidized cholesterol as a pathogen, and scramble to engulf the cholesterol. This sets up a chain of chronic inflammation, which damages the artery lining.
A healthy artery endothelium (artery lining) produces nitric oxide, which relaxes the muscle surrounding the artery, causing the artery to widen, improving blood flow through the artery. Nitric oxide also reduces inflammation and clotting within the blood vessel. An artery affected by atherosclerosis makes less nitric oxide, causing artery constriction, in addition to increased inflammation and tendency to clot.
Another fate affects the HDL particle. When blood passes through the kidneys to be filtered, the smaller HDL particle cannot be reabsorbed into the system. Instead, it passes into the urine and is lost. The HDL particle concentration drops, and the removal of cholesterol from the artery lining decreases.
The net result of this dynamic is that more cholesterol is deposited into the artery lining than is removed, causing the accumulation of cholesterol into the lining.
Atherogenic lipoproteins, or particles that can deliver cholesterol to the artery lining, include VLDL, LDL, and Lp(a). The concentration of these lipoprotein particles is more important than the amount of cholesterol they carry. These particles all have something in common: they have exactly one molecule of apolipoprotein B (also known as apoB) per particle. ApoB is the attachment protein for the liver receptor, like a key for a lock. Without apoB, lipoproteins would not be able to be reabsorbed into the liver. Since the atherogenic lipoproteins all contain exactly one apoB, we can estimate the number of atherogenic particles by counting apoB. I consider this the most important test in my lipid assessments. A person with insulin resistance will have an elevated apoB. This is why type 2 diabetic patients have a higher risk of coronary artery disease.
When your lipids are evaluated, the following tests should be ordered:
Standard lipid profile. This measures the total amount of cholesterol carried within the various lipoprotein particles in a deciliter of blood, measure in mg/deciliter:
LDL-cholesterol
HDL-cholesterol
VLDL-cholesterol
Lp(a), best measured in nmol/L (which is an indirect way of measuring the number of Lp(a) particles), but sometimes measured in mg/dL. Lp(a) is not tested in a standard lipid panel
ApoB (apolipoprotein B), the amount of apoB mass, measured in mg/dL, this is not tested in a standard lipid panel
Triglycerides, the amount of blood fat contained within a deciliter of blood. Triglycerides should be less than 70 to be physiologically normal. Elevated triglycerides are often, but not always, seen in people with insulin resistance and obesity.
Campesterol and sitosterol are plant sterols. Think of them as a type of cholesterol but made from plants, not animals. They are more atherogenic than the cholesterol we make within our bodies. Most people do not absorb plant sterols from the digestive tract. However, if we do absorb it, the ABC G5/G8 pump on the surface of the small intestine usually pumps it right back out. The ABC G5/G8 pump is like a bouncer in a bar. However, some people absorb plant sterols to excess. There is medication available to block absorption of these sterols. Plant sterols are not tested in a standard lipid panel.
There are other tests that can be ordered, but because they would not likely change my recommendation, I usually do not order them.
Target points for lipid lowering:
In my high-risk patients, or for anyone who wishes to lower their risk as much as possible to prevent vascular disease, my goals are an LDL-cholesterol is <60 and apoB <60. A study using ultrasound demonstrated that the soft part of a vascular plaque can shrink when aggressive medication is employed to drop the test numbers down this low.
In summary
Atherogenic lipoprotein particles cause vascular disease, causing an increased risk of heart attack, stroke, dementia, and other conditions. Our current lifestyle habits tend to increase cholesterol and apoB concentration, increasing the risk of vascular disease. Reducing the number of atherogenic particles by improving lifestyle and using lipid-lowering medication reduces the risk of these outcomes. I will address this on another presentation.