Cholesterol and Heart Disease

Press Release for the 1985 Nobel Prize in Physiology or Medicine

Press release

By: Nobel Assembly at the Karolinska Institute

Date: October 14, 1985

Source: Nobel Assembly at the Karolinska Institute. Press Release: The 1985 Nobel Prize in Physiology or Medicine. 〈http://nobelprize.org/medicine/laureates/1985/press.html〉 (accessed December 11, 2005).

About the Author: The Nobel Assembly at the Karolinska Institute has awarded the Nobel Prize annually since 1901 for achievements in physics, chemistry, physiology or medicine, literature, and peace.

INTRODUCTION

The Karolinska Institute's 1985 press release announced the awarding of the Nobel Prize in Physiology or Medicine to two American researchers at the University of Texas—Michael S. Brown and Joseph L. Goldstein—for their discoveries in the regulation of cholesterol. The main purpose of the press release was to outline the discoveries in cholesterol physiology and their significance to science and medicine. The release recounts Brown's and Goldstein's finding that receptors on cellular surfaces mediate the uptake of circulating low-density lipoprotein (LDL), a substance of fundamental importance in building cellular membranes, synthesizing hormones, and many other physiological functions. The researchers discovered that abnormalities in these receptors result in their inability to take up circulating LDL. As a result, high LDL levels in the bloodstream can accumulate in hard plaques on arterial walls. These plaques narrow and harden the arteries (atherosclerosis), leading to reduced blood circulation in cardiac and peripheral arteries. Advanced cases result in ischemic heart disease and myocardial infarctions or heart attacks in which sections of the heart muscle are starved of oxygen and die.

The immediate medical application of this discovery was to cases of familial hypercholesterolemia, an inherited disorder that results in circulating LDL of up to five times normal levels. Brown and Goldstein discovered that cells from individuals that were homozygous for this trait had no capacity to bind and absorb circulating LDL, while far more common heterozygous cases had impaired capability due to reduced numbers of receptors to bind LDL.

Understanding the physiology of cholesterol regulation paved the way for drug treatment of milder hypercholesterolemia cases, which constitute the vast majority of patients with elevated cholesterol. Treatments for high cholesterol now comprise the largest drug expenditure category for the U.S. health care system.

PRIMARY SOURCE

The Nobel Assembly at the Karolinska Institute has today decided to award the Nobel Prize in Physiology or Medicine for 1985 jointly to
Michael S. Brown and Joseph L. Goldstein
for their discoveries concerning "the regulation of cholesterol metabolism."

SUMMARY

Michael S. Brown and Joseph L. Goldstein have through their discoveries revolutionized our knowledge about the regulation of cholesterol metabolism and the treatment of diseases caused by abnormally elevated cholesterol levels in the blood. They found that cells on their surfaces have receptors which mediate the uptake of the cholesterol-containing particles called low-density lipoprotein (LDL) that circulate in the blood stream. Brown and Goldstein have discovered that the underlying mechanism to the severe hereditary familial hypercholesterolemia is a complete, or partial, lack of functional LDL-receptors. In normal individuals the uptake of dietary cholesterol inhibits the cells own synthesis of cholesterol. As a consequence the number of LDL-receptors on the cell surface is reduced. This leads to increased levels of cholesterol in the blood which subsequently may accumulate in the wall of arteries causing atherosclerosis and eventually a heart attack or a stroke. Brown and Goldstein's discoveries have led to new principles for treatment, and prevention, of atherosclerosis.

CHOLESTEROL—AN IMPORTANT SUBSTANCE

The cholesterol debate during the last decade may have given the public the impression that cholesterol is something you have to avoid to survive. This is, however, neither possible nor desirable: cholesterol is present in all our tissues and is produced in the body. Cholesterol is also vitally important for several of the normal processes in the body.

Cholesterol originates from two main sources—from within through biosynthesis predominantly in the liver, and from without through fat in the food. In the liver as well as in the intestine cholesterol is packeted into particles in such a way that it can be transported in the blood and lymphatic fluid. These particles are called lipoprotein—a combination of fat and proteins. There are different kinds of lipoproteins and they are classified on the basis of their density as determined by ultracentrifugation: Low Density Lipoproteins (LDL), Very Low Density Lipoproteins (VLDL) and High Density Lipoproteins (HDL). The particles transporting cholesterol circulating in the blood are LDL….

A normal healthy person has approximately 2 g cholesterol per liter plasma. The highest abnormal values, approximately 10 g per liter, are found in persons with a severe disease called familial hypercholesterolemia (FH), which is an inborn error of metabolism.

CHOLESTEROL IS FOUND IN CELL MEMBRANES AND IS CONVERTED TO HORMONES AND BILE ACIDS

Cholesterol has two main functions in the body. It constitutes a structural component in cell membranes, and it is converted to certain steroid hormones and bile salts. More than 90 per cent of the cholesterol in the body is found in cell membranes.

Each cell is surrounded by a membrane, the cell or plasma membrane. Its function is not only to be a protective coat. It also serves as a border control determining which substances are allowed to enter or leave the cell. This function is sometimes facilitated by the presence of specific receptors whereby certain molecules are efficiently trapped and taken up by the cell.

The cells either produce their own cholesterol or take up LDL circulating in the blood stream. The discovery of the LDL-receptor by Brown and Goldstein in 1973 was a milestone in cholesterol research.

Several hormones are produced from cholesterol like estrogen and testosteron, cortison and aldactone. Cholesterol is stored in cells of the adrenals and gonads and can be utilized as soon as there is a requirement for these hormones.

Cholesterol also takes part in the synthesis of vitamin D, which prevents development of rickets. Vitamin D is produced in the skin when exposed to the sun's ultraviolet light.

Another vital function of cholesterol is associated with food intake. Cholesterol is converted into bile acids in the liver and is transported via the bile to the upper intestine where the bile salts emulsify the dietary fat making it absorbable. The bile salts then return to the blood stream and are taken up by the liver and again secreted into the upper intestine. This recycling of bile acids normally limits the liver's need for cholesterol.

EXCESS CHOLESTEROL ACCUMULATES IN THE WALLS OF ARTERIES

As stated above cholesterol is of vital importance for the body. Thus, cholesterol deficiency, a rare disease, causes severe damage particularly in the nervous system. However, the most common abnormality in the cholesterol metabolism is of the opposite kind. Excess cholesterol accumulates in the walls of arteries forming bulky plaques that inhibit the blood flow until a clot eventually forms, obstructing the artery and causing a heart attack or stroke.

The accumulation of cholesterol in the arterial walls is a slow process lasting over decades. Among factors contributing and accelerating this process are high blood pressure, a high intake of animal fat in the food, smoking, stress and genetic factors.

Studies on patients with familial hypercholesterolemia (FH) by Michael S. Brown and Joseph L. Goldstein constitute founding stones for our present knowledge concerning the cholesterol metabolism. FH exists in different forms and is inherited as a monogenic dominant trait.

Individuals who carry the mutant gene in double dose (homozygotes) are severely affected. Their serum cholesterol levels are five times higher than in healthy persons, and severe atherosclerosis and coronary infarction is seen already in adolescence, or even earlier. Individuals who have inherited only one mutant gene (heterozygotes) develop symptoms later in life—at 35 to 55 years of age. Their cholesterol levels are approximately 2-3 times higher than in normal people.

PATIENTS WITH FH LACK FUNCTIONAL LDL-RECEPTORS

Brown and Goldstein studied cultured human cells (fibroblasts) from healthy individuals and individuals with FH. Like all animal cells cultured fibroblasts need cholesterol in their cell membranes. Cholesterol—in the form of LDL—was found to be taken up by highly specific receptor molecules on the cell surface—the LDL-receptor. The revolutionizing discovery was then made that fibroblasts from patients with the most severe form of FH completely lacked functional LDL-receptors. Fibroblasts from patients with the milder form of FH had fewer LDL-receptors than normal—a reduction by half.

Brown and Goldstein also discovered that the synthesis of cholesterol in normal fibroblasts was inhibited when LDL-containing serum was added to the cell culture. Fibroblasts from homozygous patients with FH were not inhibited since they lacked functional LDL-receptors. Consequently their intracellular synthesis could not be influenced.

In later studies Brown and Goldstein showed that LDL which had bound to the receptor was taken up by the cells as a LDL-receptor complex. One effect of the uptake of cholesterol is that it inhibits the manufacture of new LDL-receptors on the cell surface. A reduced number of LDL-receptors leads to a diminished LDL uptake. LDL then remains in the blood stream with the risk of accumulation in the arterial walls.

Brown and Goldstein have discovered a new, and unexpected way of regulation of cholesterol metabolism. Normally cells have a high capacity to synthesize their own cholesterol. With a low availability of cholesterol (LDL) in the blood circulation the cells increase the number of LDL-receptors on their surface. The concentration of LDL in the blood is thereby diminished. The more LDL there is in the blood circulation the easier it is for the cells to acquire it. With a high dietary fat intake an excess of LDL circulates in the blood.

THE DISCOVERIES HAVE RESULTED IN NEW APPROACHES FOR THE TREATMENT OF ATHEROSCLEROSIS

The discovery of the LDL-receptor has broadened our understanding of cholesterol metabolism considerably and explained the mechanism behind familial hypercholesterolemia.

Brown and Goldstein have used modern molecular biology techniques to show that the LDL-receptor is a glycoprotein located in the cell membrane…. The LDL-receptor defect can be one of several different kinds: in some cases the receptor is completely lacking, in others LDL binds poorly, or not at all, to receptor and in still others LDL is bound to the receptor but the LDL-receptor complex is not internalized….

The severe form of FH (homozygous) is rare, about one in a million people. The milder form of FH (heterozygous) is much more common, about one in 200-500 people. This means that in a city like Stockholm several thousand inhabitants have the disease with its associated risks of atherosclerosis and heart infarction.

Brown and Goldstein have introduced entirely new principles for treatment of FH based on their discovery of the LDL-receptor. In individuals with the milder heterozygous form of FH the number of LDL-receptors has been increased using drugs—cholestyramine and mevinolin. Such treatment has been found to lower blood cholesterol levels. In the more severe homozygous form of FH, where functional LDL-receptors are missing, medication is no therapeutic alternative. There liver transplantation has been tried. A severely ill 6 year old girl, who already had suffered several heart attacks, was given a new liver and heart simultaneously. More than six months after the operation her blood cholesterol levels were in the range of 3 g per liter compared to 12 g per liter before the liver transplantation.

The discoveries made by Brown and Goldstein have drastically widened our understanding of the cholesterol metabolism and increased our possibilities to prevent and treat atherosclerosis and heart attacks. But their discoveries have even more far-reaching implications. Coronary infarction is a major cause of death in most industrialized countries. The disease is caused by hereditary and environmental factors, which together cause a reduction of the number of LDL-receptors. This increases the blood levels of LDL and thereby the risk for atherosclerosis. Brown and Goldstein's revolutionary results have widened our horizon and holds promise for future fascinating developments. They speculate themselves about therapy with drugs that increase the number of LDL-receptors simultaneous with a lesser demand for dietary regimens … "it may one day be possible for many people to have their steak and live to enjoy it too."

SIGNIFICANCE

Brown and Goldstein received the 1985 Nobel Prize in Physiology or Medicine in recognition of work that led to widespread treatment of elevated cholesterol, which is credited with the prevention of millions of deaths and cases of disability from cardiovascular disease. Few other medical discoveries rival the understanding of cholesterol physiology in terms of fostering secondary preventive pharmaceutical treatment.

The Centers for Disease Control and Prevention (CDC) estimates that approximately 20 percent of adults in the United States suffer from hypercholesterolemia. The prevalence of high cholesterol increases with age, with the highest incidence observed in women between the ages of sixty-five and seventy-four. According to the World Health Organization (WHO), hypercholesterolemia is implicated in 56 percent of coronary heart disease cases globally, resulting in 4.4 million deaths annually. The female death rate due to high cholesterol is marginally higher than the male death rate.

When hypercholesterolemia is diagnosed, doctors generally advise patients to reduce circulating LDL cholesterol by reducing dietary cholesterol (avoiding the consumption of foods containing animal fats) and increasing exercise. This "lifestyle change" regimen can lead to weight loss, which also reduces circulating LDL cholesterol. If lifestyle modifications are not effective in reducing cholesterol levels, then drug therapy is prescribed. New guidelines issued by the Institute of Medicine in 2001 lowered the limit for what was considered to be "healthy" cholesterol levels and nearly tripled the number of Americans who are candidates for cholesterol-lowering drugs.

While there are three other classes of cholesterol-lowering drugs—niacin, fibrates, and bile acid sequestrants—HMG-CoA reductase inhibitors (so-called statin drugs, such as Lipitor, which can lower LDL cholesterol by 25 percent or more) are the most effective and well-tolerated cholesterol reducing drug class. By 2001, they comprised about 90 percent of the cholesterol-lowering drug market. Currently, statin drugs comprise either the largest or second-largest drug class in terms of expenditures for most health insurance plans. In 2005, the sales of Lipitor, the market leading statin drug, are expected to hit $10 billion. Total sales for the drug class could reach $20 billion.

Clinical trials have demonstrated that statin therapy significantly reduces the risk of coronary events for patients with elevated cholesterol levels. A study by the National Center for Health Statistics (NHCS) using data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) examined statin drug utilization by age, sex, race, or ethnicity, and selected diagnoses. The NCHS study found that between 1960 and 2000 the percent of adults with high cholesterol decreased from 33 percent to 18 percent, partly due to an increase in drug therapy, and partly due to reduced intake of animal fats among other factors. During this time the rate of statin prescriptions in ambulatory care visits tripled from 1995 to 2001 among those aged forty-five and older.

Despite a cascade of clinical trial results confirming the role of cholesterol in heart disease, such a role and the increasingly heavy use of statin drugs is still not universally accepted. The International Network of Cholesterol Skeptics (THINCS), which represents a group of physicians and medical researchers, questions the interpretation of clinical trial results by groups such as the American Heart Association and the pharmaceutical industry showing an association of cholesterol levels with incidence of heart disease. They maintain that the statistical association between cholesterol reduction using statin drugs and reduced heart attack deaths exists because of characteristics of the drugs not associated with cholesterol reduction. For example, statins appear to reduce inflammation in the arteries of the heart that can cause the buildup of atherosclerotic plaques.

Statin drugs are generally considered to be well-tolerated. However, they are associated with rhabdomyalysis (breakdown of muscle tissue), reductions in Coenzyme Q-10 (a naturally occurring antioxidant), and liver damage, particularly when taken with alcohol, non-steroidal anti-inflammatory drugs, and acetaminophen.

In spite of continuing controversy and some side effects, the treatment of hypercholesterolemia and even moderately elevated or "normal" cholesterol levels appears likely to grow further. The Nobel Prize press release reported that Brown and Goldstein themselves speculated that cholesterol treatment might allow people to eat steak without facing greater risk of dying from heart disease. As with other emerging types of drug treatment, such as the utilization of selective serotonin re-uptake inhibitors (SSRI antidepressants), conjecture abounds that pharmaceuticals could eventually be taken by people with few or no signs and symptoms of disease. At the same time, third-party payers will carefully examine such use by low-risk patients to determine if it is cost-effective in terms of preventing future complications that result in hospitalization.

FURTHER RESOURCES

Books

Beers, M. H., and R. Berkow, eds. The Merck Manual of Diagnosis and Therapy. Centennial Edition. Whitehouse Station, N. J.: Merck Research Laboratories, 1999.

Web sites

American Public Health Association. "Statin Drug Use: Age and Gender Differences." 〈http://apha.confex.com/apha/132am/techprogram/paper_81482.htm〉 (accessed November 3, 2005).

Cardiology Channel. "High Cholesterol." 〈http://www.cardiologychannel.com/hypercholesterolemia/〉 (accessed November 3, 2005).

The International Network of Cholesterol Skeptics. "Concerned Scientists Dispute New Cholesterol-Lowering Guidelines." 〈http://www.thincs.org/pressrelease82004.htm〉 (accessed January 11, 2006).