Cholesterol

Cholesterol is small molecule, one of the steroids. It is essential to life. It has also been responsible for 17 Nobel Prizes, countless pages of reports in scientific journals and the popular press, and mounting anxiety on the part of health-conscious people. Why?

The human body contains about 100 g of cholesterol. Most of this is incorporated in the membranes from which cells are constructed and is an indispensable component of them. The insulating layers of myelin wound around neurons are especially rich in cholesterol. In far smaller quantities, but no less important, cholesterol is starting ingredient for the synthesis of the steroid hormones:

• progesterone;
• estrogens;
• androgens (e.g., testosterone);
• glucocorticoids (e.g., cortisol);
• mineralocorticoids (e.g., aldosterone).

Cholesterol is also the precursor from which the body synthesizes vitamin D.

One of the major uses of cholesterol is the synthesis of bile acids. These are synthesized in the liver from cholesterol and are secreted in the bile. They are essential for the absorption of fat from the contents of the intestine. A clue to the importance of cholesterol is that more than 90% of the bile acids are not lost in the feces but are reabsorbed from the lower intestine and recycled to the liver. There is some loss, however, and to compensate for this and to meet other needs, the liver synthesizes some 1500–2000 mg of new cholesterol each day. It synthesizes cholesterol from the products of fat metabolism.

There is also an unceasing transport of cholesterol in the blood between the liver and all the other tissues. Most of this cholesterol travels as low density lipoproteins (LDLs). Each LDL particle is a sphere filled with ~1,500 molecules of cholesterol complexed with fatty acids and coated with a layer of phospholipids and a single molecule of a protein called apolipoprotein B (apoB).

Cells that need cholesterol trap and ingest LDLs by receptor-mediated endocytosis.

• High levels of LDL cholesterol lead to the development of atherosclerosis: cholesterol-rich deposits (plaques) that form on the inside of blood vessels and predispose to heart attacks.
• Cholesterol in the bile can crystallize to form gall stones that may block the bile ducts.

The level of cholesterol in the blood is measured in milligrams per deciliter (mg/dl), which is equivalent to parts per 100,000. The levels range from less than 50 in infants to an average of 215 in adults and to 1,200 or more in individuals suffering from a rare, inherited disorder called familial hypercholesterolemia. For those of us in the normal range, approximately two-thirds of our cholesterol is transported as LDLs. Most of the rest is carried by so-called high density lipoproteins (HDLs).

Because of their relationship to cardiovascular disease, the analysis of serum lipids has become an important health measure.

The table shows the range of typical values as well as the values above (or below) which the subject may be at increased risk of developing atherosclerosis.

• Total cholesterol is the sum of
  • HDL cholesterol
  • LDL cholesterol and
  • 20% of the triglyceride value
• Note that
  • high LDL values are bad, but
  • high HDL values are good (because HDL cholesterol transports cholesterol from the tissues back to the liver where it is secreted in the bile).
• Using the various values, one can calculate a
  cardiac risk ratio = total cholesterol divided by HDL cholesterol
• A cardiac risk ratio greater than 7 is considered a warning.

In May of 2001, a panel of the National Institutes of Health recommended a more aggressive attack on reducing cholesterol levels in the U.S. population. In addition to a better diet and more exercise, they urged that many more people at risk of developing heart disease, such as

• smokers
• diabetics
• people with high blood pressure and/or
• obesity

There are several types:

• drugs that interfere with the ability of the liver to synthesize cholesterol by blocking the action of the enzyme HMG-CoA reductase. These are the "statins", e.g., lovastatin (Mevacor®), pravastatin (Pravachol®), atorvastatin (Lipitor®).
• insoluble powders ("colestipol", "cholestyramine") that bind to bile acids in the intestine so that instead of being reabsorbed they are eliminated in the feces. In compensation, the liver increases its consumption of blood-borne cholesterol. The main drawback to these drugs is that they are gritty powders and must be consumed in rather large amounts.
• nicotinic acid (niacin);
• "fibric acids" such as gemfibrozil and clofibrate.

Careful attention to diet may by itself lead to a reduction in cholesterol levels. In one study, men with high (>265 mg/dl) levels were able to lower these an average of 3.5% (10 mg/dl) by diet alone. Their diets were low in fat as well as low in cholesterol, and it was not — and still is not — clear as to what aspect of the diet contributed to the modest reduction. Cholesterol is made from fat and lowering the proportion of fat in the diet will probably help. Favoring unsaturated fats over saturated fats appears to be beneficial. There is little evidence that lowering one's intake of cholesterol is, by itself, useful. An average intake of cholesterol of 300–500 mg per day is joined in the intestine by several times that amount that has been synthesized by the liver and appears to have little or no effect on blood levels of cholesterol. So when choosing between the pat of butter and the pat of margarine, it is not the 30-odd mg of cholesterol in the butter (vs. 0 in the margarine) but its high content of saturated fat (over 3 times that in the margarine) that is probably significant.