How Antioxidant Nutrients Protect Against Heart Disease:
Part II. The role of lipoproteins

by Richard A. Passwater, Ph. D.

Those seeking to prevent heart disease and live longer by relying on low-cholesterol diets must be dismayed by the recent studies reporting that even if they are successful in lowering their blood cholesterol, the average lifespan will only be increased by eight months. [1] And that is the higher projection of recent studies, the lower projection is less than three months life expectancy increase. [2-4] These studies also show that if all causes of heart disease were eliminated, the average lifespan would be increased by only three years. The reason given is that the diseases of aging would still limit lifespan.

That may be true if the approaches used to prevent heart disease would not effect the aging of other organs and systems. Unfortunately, this is the situation when only the cholesterol approach is implemented. However, one very effective approach to preventing heart disease also protects against the effects of aging and protects against many other diseases including cancer. Antioxidant nutrients are our most effective weapons against heart disease. They help us add ten to fifteen "good" years to our lifespans by protecting us from the major killer diseases and postponing the diseases of old age as well.

Thus, we have two distinct approaches and goals in preventing heart disease -- the cholesterol approach which produces limited results and the antioxidant approach which produces many major health benefits. But this does not mean that the two approaches are mutually exclusive. It is not a case of one approach or the other. Dietary cholesterol and fats are certainly not THE causes of heart disease but they are significant factors for the approximately twenty percent lacking adequate lipoprotein compensatory mechanisms.

As we will see later, saturated fats, more than dietary cholesterol, have some effect on blood cholesterol levels. This is because fats lead to decreased LDL receptors in cells which result in more cholesterol remaining in the blood instead of being pulled into the cells. Still, in the normal healthy person, dietary fats do not have a significant effect on blood cholesterol levels.

The classical risk factors all together -- smoking, high blood pressure and high blood cholesterol still account for less than half of heart disease deaths. My point is that concentrating on the minor factors exposes you to risk from the major cause of heart disease -- antioxidant deficiencies!

You can actually combine the "prudent" measures with the antioxidant "alternative " measures for even greater protection if you so choose. If you wish to eat low-cholesterol, low-fat diets -- go ahead -- but also get a balance of vitamins and minerals. This is the theme of "The New Supernutrition." [5] However, many people will find that it is a waste of time, effort and enjoyment to worry about cholesterol because their bodies compensate for both dietary cholesterol changes and blood cholesterol changes. The major compensatory mechanism is the lipoprotein cholesterol transport system, which is the main topic of this article.

This article is the second of a series describing how antioxidant nutrients prevent heart disease. The main emphasis of this article is building the background needed to understand why cholesterol itself does not initiate heart disease, but how it can become an important factor when free radicals alter the cholesterol-carrying lipoproteins in the blood. Part I of this series reviewed recent studies showing antioxidant nutrients such as vitamin E, vitamin C, beta-carotene, selenium and pycnogenol do indeed protect against heart disease. [6]

Of particular note was the multi-national World Health Organization study by Dr. Fred Gey of the University of Bern (Switzerland) confirming vitamin E deficiency is more closely linked to death from heart disease than high blood cholesterol or high blood pressure. [7] Low vitamin E blood levels could predict 62 percent of heart disease deaths, whereas all of the classical risk factors combined explained less than half of heart disease deaths.

Vitamin E and the other antioxidant nutrients are protective in many ways that involve both steps in the typical heart disease process. The first step is plaque formation which narrows the artery openings. This is the atherosclerosis step. The second step is when a blood clot forms in a coronary artery that has been narrowed by atherosclerotic plaque. This is the typical heart attack called coronary thrombosis. Figure 1 depicts the two components of this common form of heart disease. [8]

As an example of antioxidant nutrient protection, vitamin E protects the artery lining against injury, reduces the formation of compounds that can cause plaque formation, improves the level of HDL cholesterol to carry away cholesterol, and keeps the blood platelets from clumping so that clots are not formed.

The anti-clotting factor is especially important, and I have discussed it frequently. The first action most cardiologists take today is to prescribe aspirin. Now aspirin doesn't lower cholesterol or blood pressure, but studies show that it reduces heart attacks by 30 to 50 percent by reducing blood clotting. Unfortunately, aspirin affects the clotting process too much, and some people develop serious gastrointestinal bleeding.

Vitamin E, on the other hand, helps repair blood platelets damaged by being squeezed through narrowed arteries. Vitamin E does not interfere with the same enzyme that aspirin interferes with which results in a longer time required to form a clot. Thus, vitamin E normalizes clotting time to prevent coronaries without causing internal bleeding. [9] Vitamin E works in two ways to improve clotting. One way may be similar to the manner in which aspirin works, but vitamin E is completely safe and far superior.

An interesting point is that this information has been elucidated since my 1974 epidemiological study showing that vitamin E protects against heart disease. [10-12] My data showed a very strong protective effect, but it wasn't until we learned much more about heart disease that we began to understand the many ways in which vitamin E works.

This article will examine how preventing low-density lipoprotein from oxidizing greatly reduces the formation of arterial plaque. However, first we should review lipoproteins and their role in transporting cholesterol.


Cholesterol is a fatty material and is insoluble in blood. Most of the cholesterol in the blood is present as a cholesterol ester. An ester is produced when a free fatty acid -- in this case, normally linoleic acid -- is combined with the cholesterol molecule. Both free cholesterol and cholesterol esters are "fatty" type compounds.

Blood is primarily water containing lots of proteins and electrolytes. Remember oil (fat) and water don't mix. Chemists call fats, oils and other fatty materials "lipids." Soap can dissolve oil in water because one end of a "soap" molecule is water-soluble and the other is fat-soluble. Like dissolves like. The body overcomes the problem of transporting cholesterol in blood, not by dissolving it in a soap, but by constructing special carriers. These carriers have both lipid regions and protein regions, and are thus called "lipoproteins."

Lipoproteins are not compounds -- they are macromolecular complexes. That is, they are groups of different compounds arranged in a specific and orderly fashion so as to accomplish a function. They are held together by patterns of electronic charge distributions rather than being rigidly bonded. For practical purposes, lipoproteins may be considered to be particles. The important point is that lipoproteins are not specific compounds, but complexes of compounds that act as a particle.

Lipoproteins typically consist of a lipid core of nonpolar triacylglycerol and cholesterol esters surrounded by a layer of polar phospholipids, cholesterol and apolipoproteins. Apolipoproteins will be discussed in the next section. Figure 2 represents a "generic" lipoprotein. [13]

The hydrophobic (water-avoiding) "tails" of the outer lipid monolayer are oriented to the oily interior of cholesterol esters as shown in figure 2. The polar hydrophilic (water-seeking) heads of the outer monolayer lipids are exposed to the surface of the particle, allowing it to be solvated by water.

The various lipoproteins have different roles in transporting cholesterol, triglycerides and other fatty compounds. A triglyceride is a fat that contains three fatty acids attached to a glycerol molecule. All lipoproteins are composed of the same types of compounds, but the percentage of each varies.

You know from experience that muscle (protein) is more dense than fat, and that fat is less dense than water. Lean athletes do not float in water as well as people with a large percentage of body fat. With lipoproteins, the higher the percentage of fat (in the form of triglycerides) the lower the density. Or putting it another way, the higher the percentage of protein in a lipoprotein, the higher its density.

Lipoprotein density has been a classical way to describe the various lipoproteins. They are readily separated in a centrifuge because of their greatly different densities. There are six clinically significant lipoproteins, and four of them are named according to their relative densities. The higher their density, the more beneficial the lipoprotein.

The four common lipoproteins are, in descending order, high-density lipoprotein (HDL), low-density lipoprotein (LDL), intermediate-density lipoprotein, (IDL), and very-low-density lipoprotein, (VLDL). Figure 3 shows how the percentage of protein increases as the diminishing lipid content also decreases the size of the lipoprotein. Table 1 lists the composition of these lipoproteins. [13]

Another clinically significant lipoprotein is lipoprotein(a) [Lp(a)] which is closely related to LDL. Lp(a) is very important and will be discussed in detail in Part IV of this series.

The sixth major lipoprotein is not involved in the transport of the cholesterol that we are primarily concerned with in heart disease. This sixth lipoprotein is called a "chylomicron" and is involved with transporting fats and cholesterol from the intestine to the liver.


The protein portions of lipoproteins are called "apolipoproteins" or "apoproteins." I prefer the term "apolipoprotein" because it is a narrower description than the more general "apoprotein." HDL contains around 60 percent apolipoproteins, whereas the fat-filled chylomicrons are only about one percent apolipoprotein. (See figure 3) Apolipoproteins are designated first by the letter of the class they belong to (A through E) and then by a Arabic or Roman numeral to designate the sub-class. Table 2 describes nine common apolipoproteins. [13] Common usage simply refers to apolipoproteins by the prefix "apo" followed by the appropriate letter or letter/number designation. Thus, apolipoprotein A and apolipoprotein B are usually called apoA and apoB, respectively.

Do not confuse "lipoprotein(a)" and "apolipoprotein A." The two are also written as Lp(a) and apoA. They are not the same critter. Apolipoprotein A (apoA) is a component of Lipoprotein(a) [Lp(a)]. Hang in there. I'll clarify this when we discuss Lipoprotein(a) in Part IV.

Some apolipoproteins are integral components, whereas others are free to transfer to other lipoproteins. The integral apolipoproteins usually penetrate through the various regions of the complex, whereas the transferable lipoproteins are usually peripheral to the surface. In figure 2, apolipoprotein C is shown as a peripheral apolipoprotein, while apolipoprotein B is shown as an integral apolipoprotein. [13]

Lipoprotein Function

As mentioned earlier, the various lipoproteins have different roles in cholesterol transport. In this article, I will discuss only the roles of the four lipoproteins named according to their densities. It is important to understand the role of these cholesterol transporters, if we are to understand why the total blood cholesterol measurement is not important in heart disease and why other factors are important.

The liver converts excess food products into triglycerides and loads these triglycerides into VLDL particles for transport to other cells. These cells may "burn" the triglycerides for energy or store them as fat. During transport, VLDL has some of its triglycerides broken down to free fatty acids and glycerol by an enzyme called lipoprotein lipase, and a helper protein called apoC-2.

Cholesterol is also loaded into VLDL by the liver. The cholesterol is either manufactured by the liver or absorbed from food. If more cholesterol is returned to the liver by lipoproteins, then the liver decreases its own cholesterol production.

In a process that is unimportant to us here, VLDL becomes a "VLDL remnant" and then IDL. As depicted by figure 3, IDL is a smaller complex than VLDL, but contains the same quantity of cholesterol. Thus, in comparison to VLDL, IDL has a higher percentage of cholesterol. IDL also has a smaller quantity of triglyceride and a lower percentage of triglyceride than VLDL.

When still more triglycerides are removed, IDL becomes LDL. Relative to VLDL, LDL is cholesterol-rich even though both contain about the same quantity. The big difference is that triglycerides have been removed and the particle has become smaller. See figure 3.

LDL contains apolipoprotein B-100 (apoB-100). I keep straight which apolipoprotein goes with LDL by keying on "B" for "Bad" and with a capital "B." Typical LDL particles are about 22 nanometers in diameter and contain about 1,500 molecules of cholesterol esters, surrounded by a lipid sheath having approximately 800 molecules of phospholipids and 500 molecules of unesterfied cholesterol.

LDL carries its cargo to cell membranes. Receptors on the cell surface latch on to the LDL particle and carry it through the membrane and into the cell interior, where the LDL cargo is unloaded. After unloading its cargo, the LDL particle is transported to lysosomes within the cell, which disassemble the LDL into its unassociated components.

The LDL receptor is an important factor in this process and will be discussed more fully in Part IV. It will suffice here to point out that the number of LDL receptors on each cell determines how many LDL particles -- with their cholesterol cargoes -- are removed from the blood. The number of LDL receptors is partially dietary-dependent and partially genetic.

In Part IV, we will examine the role of diet in LDL receptor production and its role in blood cholesterol level. But the important thing to keep in mind here is LDL, LDL receptors and the amount of cholesterol carried into the cells are only a part of the blood cholesterol transport story. The role of HDL is more important as HDL is able to overcome the problems caused by too many LDL particles and too much LDL-carried cholesterol.

HDL is produced in the liver and carried by the blood. HDL is a round, flat, coin-like molecule when it leaves the liver. Its structure is flexible -- like an empty sack that can be filled. A filled HDL molecule is spherical in shape.

Unlike LDL which has only a single apolipoprotein, HDL has two major apolipoproteins and five minor apolipoproteins. The major HDL apolipoproteins are apoA-I and apoA-II. The minor HDL apolipoproteins are apoC-I, apoC-II, apoC-III, apoD and apoE. It will suffice if you can remember that HDL contains apoA and LDL contains apoB.

HDL, like LDL, uses a receptor on the cell surface to help it work. The mechanism of this receptor has only recently been elucidated. When HDL contacts the HDL receptor on the cell surface, the HDL receptor sends chemical messengers to the cell interior. These chemical messengers carry excess cholesterol to the HDL receptor, which then loads the cholesterol into HDL. As the flat HDL particle fills up with cholesterol, it swells and breaks contact with the HDL receptor. This newly discovered process will be discussed in more detail in Part IV.

Thus, the role of HDL is to scavenge for excess and unwanted cholesterol and take it back to the liver so that the liver doesn't have to make so much cholesterol. If you picture LDL particles as delivery trucks toting cholesterol to the cells and HDL particles as garbage trucks hauling cholesterol away from the cells -- an analogy that I originated in 1976 to help the public visualize this process -- you will be close enough. [8]

The practical lesson then seems to be that if you have enough HDL, then it won't matter how much LDL you have. However, there is a fly in the ointment! If we only had LDL and HDL particles to deal with, then the HDL-to-LDL ratio would be the determining factor in cholesterol build up. However, when LDL particles become oxidized, we have a new problem. Oxidized LDL is a horse of a different color than LDL.

Oxidized LDL is taken up by LDL receptors uncontrollably and contributes to invasive foam cell production. Thus, oxidized LDL becomes a major cause of plaque build up, independent of the otherwise prerequisite damage to the artery lining. Now that we have isolated a significant factor in the first step in the common form of heart disease, we can focus on preventing this problem. The good news is that the antioxidant nutrients protect LDL from being oxidized.


1. Goldman, Lee; Weinstein, Milton C. and Tsevat, Joel. Circulation (April 1991)

2. The Cholesterol Myth Moore, Thomas J. Atlantic Monthly 37-57 (September 1989)

3. Heart Failure Moore, Thomas J. Random House, NY (1989)

4. Rose, Geoffrey and Shipley, Martin. Lancet 335:275-7 (1990)

5. The New Supernutrition. Passwater, Richard A. Pocket Books, NY, (1991)

6. How Antioxidant Nutrients protect against heart disease: Part I. Passwater, Richard A. Whole Foods ( ) - (April 1991)

7. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Gey, K. Fred; Puska, Pekka; Jordan, Paul and Moser, Ulrich K. Amer. J. Clin. Nutr. 53:326S-334S (Jan. 1991)

8. Supernutrition For Healthy Hearts Passwater, Richard A. Dial Press, NY (1977)

9. Aspirin and Vitamin E: More than one way to protect against heart disease. Passwater, Richard A. Wholw Foods 12-14 (June 1988)

10. Heart Study of 70-79 Year Olds. Passwater, Richard A. Prevention 28(2) 61-8 (Feb. 1976)

11. Heart Study of 60-69 Year Olds. Passwater, Richard A. Prevention 28(4) 107-113 (April 1976)

12. Heart Study of 50-59 Year Olds. Passwater, Richard A. Prevention 28(5) 111-5 (May 1976)

13. Harper's Biochemistry, 21st Ed. Murray, R. K., et al., Appleton & Lange, Norwalk, CT (1988)

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