Cholesterol is not water-soluble enough to dissolve in the blood, so it is carried in lipoproteins. Lipoproteins consist of the following parts:
A core of fats (also called triglycerides), cholesterol esters (cholesterol linked to fatty acids), and fat-soluble vitamins.
A membrane of phospholipids and small amounts of free cholesterol.
A protein called an "apoprotein" that weaves through the phospholipid membrane.
The lipoprotein is basically a carrier for cholesterol, fat, and other fat-soluble nutrients like vitamins A, D, E and K, and coenzyme Q10.
If we think of the lipoprotein as a bus, the "core" is the passenger section, and the fats, cholesterol esters, and vitamins are the passengers.
The phospholipid membrane is the outside of the bus. Phospholipids contain fat-soluble fatty acids that face inwards toward the fatty core and water-soluble phosphate groups that face outwards toward the blood. We could therefore think of the phosphate groups as the tires, since they allow contact with and movement through the blood, just like the tires of a bus allow contact with and movement on the road.
The apoprotein is like the driver. It interacts with specific receptors on the surface of cells, so it determines where the lipoprotein goes, where it decides to park, and where it lets the passengers out.
Chylomicrons, VLDL, IDL, and Lp(a)
We hear about HDL and LDL the most, but there are a number of other lipoproteins, such as chylomicrons, VLDL, IDL, and Lp(a).
HDL and LDL stand for "high-density lipoprotein" and "low-density lipoprotein." VLDL stands for "very low-density lipoprotein," IDL stands for "intermediate-density lipoprotein" and Lp(a) stands for "lipoprotein (a)."
The functions of these lipoproteins are easiest to understand if we think about them in the context of the lipoprotein cycle.
The Lipoprotein Cycle
Our intestines package cholesterol, fats, and fat-soluble nutrients into chylomicrons.
The apoprotein that these lipoproteins get is apoB-48. It is a shortened form of apoB-100, being approximately 48 percent as long. The longer version, apoB-100, is found in VLDL, IDL, and LDL. All of the apoB-containing lipoproteins can be taken into the liver by the LDL receptor.
Chylomicrons travel from the intestines to the blood through the lymphatic system. Once in the blood, they deliver cholesterol, fat, and other nutrients to various tissues. These tissues "digest" the chylomicrons into chylomicron remnants, and the liver takes up the remnants very quickly through the LDL receptor.
The liver repackages the fat, cholesterol, and fat-soluble nutrients into VLDL and sends it out into the blood armed with the valient apoB-100.
The VLDL delivers cholesterol, fat, and fat-soluble nutrients to other tissues much in the same way that chylomicrons do. These tissues "digest" it progressively into VLDL remnants, then into IDL, and finally into LDL. The liver takes up some VLDL remnants and IDLs through the LDL receptor, but most of them get digested into LDL.
Most of the LDL gets taken up into the liver by the LDL receptor. A variety of other tissues have smaller amounts of the LDL receptor and therefore take up whole LDLs in lower quantities.
How do LDL and HDL Affect Atherosclerosis?
LDL that does not get taken up into cells tends to oxidize. The polyunsaturated fatty acids (PUFA) in its membrane get damaged by free radicals, and then they proceed to damage the protein in the surface, and finally the fatty acids and cholesterol in the core.
Once LDL oxidizes, it can invade the arterial wall in areas that experience disturbed blood flow, like the points were arteries curve or branch. These areas, especially in people who do not exercise enough, are permeable to large molecules. Oxidized lipids cause them to attract white blood cells and initiate an inflammatory cascade that produces arterial plaque. For more on this process, see my article on the causes of heart disease.
The liver also secretes HDL particles that contain ApoA-I. When they first leave the liver, they consist of the apoprotein and some phospholipids, but no fatty core.
HDL particles can extract free cholesterol from cell membranes and attach it to fatty acids, producing cholesterol esters. They generally pass this off to LDL and other apoB-containing proteins in exchange for fats, also called triglycerides, and fat-soluble vitamins such as vitamin E. The result is that, over time, HDL tends to be rich in fats and vitamin E, while the other lipoproteins, especially LDL, are rich in cholesterol.
ApoB is not the only apoprotein that can interact with the LDL receptor. HDL and most other lipoproteins contain ApoE, which also binds to the LDL receptor, so it is possible for the liver to take up choleterol-enriched HDL directly through this receptor.
HDL delivers vitamin E to the endothelial cells that line the blood vessel wall, as I have described in this article.
Both HDL and isolated Vitamin E supppress the ability of these cells to oxidize LDL with free radical-generating enzymes and also suppress their production of inflammatory molecules that attract the white blood cells that invade the arterial wall to form arterial plaques.
Much has been made of the "reverse cholesterol transport" mechanism whereby HDL extracts cholesterol from arterial plaques, but if HDL truly has any importance in atherosclerosis its antioxidant and anti-inflammatory properties are probably much more important. The cholesterol HDL extracts from plaques and other tissues tends to be passed off to LDL rather than to the liver directly, and the plaques are already well-formed by the time any cholesterol is extracted from them. By contrast, the prevention of LDL oxidation and the invasion of white blood cells attacks atherosclerosis at its earliest stages of development before the plaques are formed.
What is Lipoprotein (a) or Lp(a)?
Lipoprotein (a), abbreviated Lp(a), is essentially a subset of LDL. Apo(a) - not to be confused with the ApoA in HDL - binds LDL particles, which also contain ApoB-100. While all LDL particles contain a single molecule of ApoB-100, only some of them are associated with Apo(a).
Lp(a) is a strong and independent risk factor for atherosclerosis and is found in arterial plaque. One hypothesis put forward in the late 1980s suggested that Lp(a) promotes blood clotting by inhibiting an enzyme that breaks down clotting factors. Lp(a) inhibits this enzyme in a test tube, but it also produces many anti-clotting action in test tubes. Humans with higher Lp(a) levels have increased bleeding times, suggesting that Lp(a) does not promote blood clotting in the live person.
More recent research has shown that virtually all the LDL containing oxidized phospholipids in the blood is associated with Lp(a). Moreover, oxidized LDL transfers oxidized phospholipids from its membrane directly to the Lp(a) particle. Thus, Lp(a) appears to be a marker for oxidation of the LDL membrane, although it is possible that Lp(a) also picks up oxidized phospholipids from the membranes of cells, such as the endothelial cells that line the blood vessel wall.
The Importance of the LDL Receptor to Heart Disease
Evidence from genetic mutations strongly suggests that poor functioning of the LDL receptor is one of the most important causes of heart disease.
Familial hypercholesterolemia results from either a defective LDL receptor or a defective ApoB protein that cannot bind the LDL receptor. In either case, the result is that cells cannot take up LDL from the blood. The LDL accumulates and over time it oxidizes.
People with familial hypercholesterolemia have markedly increased LDL levels and develop atherosclerosis much earlier than the rest of the population. In youth and middle age, when most other people do not yet have advanced atherosclerosis, they have a much higher rate of heart disease.
People with two copies of the defective LDL receptor gene generally develop atherosclerosis and heart disease in early youth if untreated, and cases have been documented where 18-month-old infants have suffered heart attacks from atherosclerosis of the coronary arteries.
On the other hand, people with genetic defects in an enzyme that degrades the LDL receptor called PCSK9 have a greatly reduced risk of heart disease. Over two percent of African Americans have a mutation that deletes this enzyme - those possessing this mutation have an 88 percent reduced risk of heart disease. This constitutes an almost complete abolition of heart disease, despite the fact that this population has a high rate of diabetes, high blood pressure, and smoking.
Among 85 African Americans with this mutation monitored over the course of 15 years, only one had a heart attack. He had high blood pressure, was obese, and was a smoker. He had an incredibly low level of LDL - only 53 mg/dL - but had incredibly high levels of Lp(a), in the 95th percentile for his race and sex.
If Lp(a) is indeed a marker for oxidation of phospholipids, especially for those in the LDL membrane, this case would seem to represent strong evidence that it is not the amount of LDL in the blood that matters, but its rate of oxidation.
On the other hand, the near abolition of heart disease in a population with this mutation suggests that the most critical factor in preventing LDL oxidation is robust expression of the LDL receptor and rapid clearance of LDL from the blood.
Another critical factor for the rate of LDL oxidation is likely to be the intake of the polyunsaturated fatty acids (PUFA), which are highly vulnerable to oxidation. I have written about this in the first of my two-part PUFA Report series, How Essential Are the Essential Fatty Acids?, and will write more extensively about this issue in the second PUFA Report, which, along with the Thyroid Toxins report, is part of my Special Reports series.
You can also peruse the references, share this article, or leave a comment below.
Read more about the author, Chris Masterjohn, PhD, here.
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