cholesterol

cholesterol Many people are now aware of their own blood cholesterol level, have it measured regularly and eat diets high in polyunsaturates. This is because they know that high cholesterol levels in the blood, and fat-rich diets, are likely to lead to heart attacks and strokes, particularly in later life. Some also know that the narrowing of arteries, particularly the coronary arteries, is due to the deposition of atherosclerotic plaques, made largely of cholesterol, on the walls of the vessels. Narrowing of the arteries reduces the flow rate, especially as flow depends on the fourth power of the radius. Thus, at a given pressure, reducing the radius to one half of normal would reduce the flow rate to one sixteenth of the original value. Adequate flow can then only be maintained by a rise in blood pressure.

The importance of cholesterol in the body can be gauged from the words of Brown and Goldstein in their Nobel Prize Lecture in 1985. They described cholesterol as the ‘most decorated’ molecule in biology, as no less than 13 Nobel awards had been made to those who spent their lives studying the substance, adding that ‘the property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal’.

Cholesterol was first isolated from gallstones in 1784. It is a neutral lipid, a sterol, and an important constituent of cell membranes. Cholesterol is obtained through the diet and synthesized in the body, in the liver and the intestine. When the intake is high, synthesis is suppressed. The cholesterol molecule has 27 carbon atoms, yet the synthesis of this complex molecule is from 2-carbon fragments (acetyl CoA) in a very complex biosynthetic process. Cholesterol is the necessary precursor of several sterol (steroid) hormones, such as the sex hormones testosterone and oestrogens, and the adrenal steroid hormones, including cortisol. Not surprisingly — remembering that cholesterol was found first in gall stones — cholesterol is used to make bile salts, the constituents of bile which take an essential part in fat absorption from the gut.

To understand how atherosclerotic plaques become deposited in arteries it is necessary to understand how the highly insoluble cholesterol is moved about the body. The agents which transport cholesterol are the lipoproteins — consisting, as their name implies, of a lipid and a protein component. Fats and cholesterol absorbed from the diet are transported as ‘chylomicrons’ from the intestine to the liver, where the fats are rapidly metabolized, and cholesterol is incorporated into low density lipoprotein (LDL) along with phospholipid molecules and one molecule of a huge protein called B-100. LDL is the main cholesterol transporter, transferring it from the liver to all other parts of the body. Since cholesterol is an essential component of all cell membranes it will be needed anywhere new cells are being formed.

The B-100 protein is a key component of LDL, as it is the molecule that is recognized by LDL receptors in the membrane of all cells. After this recognition, the LDL complex is internalized and broken down in the cell, which thus has its vital supply of cholesterol delivered to it. The LDL receptor is recycled back to the membrane to wait for another LDL. When the supply of cholesterol is plentiful the LDL receptors are ‘down regulated’ (their numbers are reduced), leaving low density lipoprotein circulating in the blood with its potentially lethal cargo of cholesterol. Eventually the cholesterol is deposited in a variety of sites, including the skin, but it is the deposition in blood vessels that leads to the start of atherosclerotic disease.

These processes were worked out in the researches of Brown and Goldstein in the 1970s from studies on patients with familial hypercholesterolamia — excessively high blood cholesterol. In this genetic disease, LDL membrane receptors are absent, so the uptake of LDL into cells is prevented. Heterozygotes (who have inherited one normal gene and one gene for this disease from their parents) have only half the normal number of LDL receptors. Normal persons have about 175 mg cholesterol per 100 ml of blood plasma, while those with the disease have over 600 mg/100 ml and heterozygotes about 300 mg/100 ml. Homozygotes with the disease usually die in infancy of coronary artery occlusion.

Alan W. Cuthbert

See also bile; fats; gall bladder.