J Leonard Dixon

There is no other molecule that instills more anxiety in humans than cholesterol. Go to the doctor and if he or she tells you that your blood cholesterol is too high, you will begin to worry about your health and the possibility of future problems with heart disease.

While teaching my class in nutrition and health over the past twenty-five years, I have attempted to give a more balanced view of cholesterol and the only way to do this is to explain what cholesterol does. The way I do this is to compare plant cells and human cells. Plant cells have a membrane that surrounds every cell, but in addition, plant cells have an exterior cell wall that is thicker than the cell membrane underneath it. Human cells do not have a cell wall, and therefore, their cell membranes need to be strengthened. The way mammalian cells strengthen their membranes is to insert cholesterol into them. The slide below shows how I envision how cholesterol plays a role as a structural molecule. Cholesterol has 4 rings that can be stacked on top of each other in the membrane, just like a common building material, the cinder block! The next slide shows cholesterol situated in in the membrane. When cholesterol is in the membrane, it promotes organization and strengthens it.

Early studies showed that cholesterol in the membrane prevents movement of the fatty acyl chains of phospholipids in the membrane, a process that is called fluidity. When phospholipids are held in place, the membrane is more rigid, thus stronger. In the red blood cell membrane, there is approximately 0.9 cholesterol molecules for every phospholipid molecule. In other types of cells, there is about 0.25 to 0.5 cholesterol molecules per phospholipid molecule. However, in brain, the myelin sheath that surrounds nerve cells is rich in cholesterol as it contains about 1.3 molecules of cholesterol per phospholipid molecule.

The greater the amount of cholesterol in a membrane, the less water, glucose, glycerol, sodium, potassium, and other small molecules that can diffuse through the membrane.

Additionally, cholesterol in the membrane is important for certain proteins in the membrane to function properly.

The cholesterol molecule emerged early in evolution and because of it properties, it was used by early organisms for other purposes besides making the membrane stronger. One of the other purposes of cholesterol is to supply the starting molecule for the synthesis of the steroid hormones. Therefore, testosterone, estrogen, cortisol, progesterone, vitamin D, and many other steroid hormones are all made from cholesterol.

A third major function of cholesterol in the body is that it is used in the synthesis of the bile salts, which are secreted into the lumen of the intestine to solubilize lipids from foods. Without bile salts the efficiency of the uptake of dietary lipids would be greatly reduced. A fourth function is that cholesterol Is required for neuron function and the process of learning and the establishment of memory.

Therefore, cholesterol plays several important roles in the body and we would not be able to survive without it.

How much cholesterol is in the body?

A 70 kg male has about 140 g of cholesterol in his entire body of which 32 g (22%) are in the brain and nerves, 22% is in adipose, connective tissue and blood, 21% is in the muscle, and the remaining 35% is distributed throughout the other tissues. To put the amount of cholesterol in the diet into perspective, most Americans consume 100 to 500 mg of cholesterol per day.   An intake of 200 mg represents 0.2g/140g of the cholesterol in the body; this dietary cholesterol represents 0.14 % of the cholesterol in the body of a 70 kg male.  (Values from Table 2.1, p. 7, of “Cholesterol,” by John R. Sabine, 1977, Marcel Dekker, New York)

If cholesterol is a such an important and necessary molecule, why is it so bad for us?

Cholesterol is bad for us when it builds up in the wrong place. One of those places is the blood where cholesterol is carried mostly in LDL particles.   For most of us, for most of our lives, there is no problem with cholesterol in the blood. But with age the number of the LDL receptors in cells declines (like many other functions decline with age) and the LDL concentration in blood builds up (See diagram of this below).  With increased LDL in blood, over time, the LDL particles can enter the artery wall and start to build up within the wall. Therefore, cholesterol also builds up within the artery wall and can become so concentrated that cholesterol crystals begin to form. At some point this becomes severe, and with the occurrence of several other events, may cause the blockage of the major conduit arteries (coronary arteries) in the heart, causing a heart attack.

So for the most part, the system that controls cholesterol in the body works fine until we start to get into our 50s or older. Remember, up until recently, most humans did not live longer than 50 years of age. Therefore, having the cholesterol regulatory system break down after age 50 had little effect on human evolution and survival. Of course, with the consumption of certain diets, the blood cholesterol can be driven higher, and then problems with cholesterol regulation occur much earlier than 50 years old. Also, as was observed with patients who had familial hypercholesterolemia (FH), or in patients with other hyperlipidemias, the system that controls cholesterol can be genetically disturbed and cause heart attacks even in young humans.

How does diet affect the cholesterol regulatory system in humans?   How does high LDL cause the blockage of arteries?

These are extremely complex questions and they are still controversial,  We will put this discussion off until we discuss statins in a later chapter.

To be honest, the precise structure of cholesterol in membranes is still being studied and debated. For example, cholesterol and sphingomyelin are closely associated and form 1:1 dimers in the membrane. Also, the membrane contains different regions of organization and cholesterol is required to form these distinct regions.  Cholesterol is crucial to the formation of the correct orientation of membrane proteins in the membrane by providing hydrophobic regions and changing the membrane thickness in certain regions of the membrane.  A recent review of this topic is presented in:

Garth L. Nicolson, The Fluid—Mosaic Model of Membrane Structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years.  Biochimica et Biophysica Acta 1838 (2014) 1451–1466.

http://www.sciencedirect.com/science/article/pii/S0005273613003933

Cholesterol in the Brain

In the past several years, studies have provided evidence that dysfunctional cholesterol metabolism in the brain may be involved in Huntington’s disease. Neurons themselves have low rates of cholesterol synthesis and they obtain most of their cholesterol from nearby cells called astrocytes (See figure below). The cholesterol needs to be shuttled to the neuron by ApoE containing lipoproteins. Without adequate cholesterol, proper myelin and new nerve connections cannot be formed during the learning process.  The role of cholesterol in the brain and in other brain conditions such as Alzheimer’s disease is just being studied in great detail.

The figure below was adapted from:  Marta Valenza and Elena Cattaneo, Emerging roles for cholesterol in Huntington’s disease, Trends in Neurosciences, September 2011, Vol. 34, No. 9, pages 474 – 486.

http://www.sciencedirect.com/science/article/pii/S0166223611000932