cholesterol

Cholesterol Why it’s so important to manage your cholesterol levels.

[cholester(in), former name for cholesterol (CHOLE- + Greek stereos, solid + -IN) + -OL¹ (so called because it was first found in gallstones).]

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A cyclic hydrocarbon alcohol commonly classified as a lipid because it is insoluble in water but soluble in a number of organic solvents. It is the major sterol in all vertebrate cells and the most common sterol of eukaryotes. In vertebrates, the highest concentration of cholesterol is in the myelin sheath that surrounds nerves and in the plasma membrane that surrounds all cells.

Cholesterol can exist either in the free (unesterified) form (see structure below) or in the esterified form, in which a fatty acid is

Cholesterol, together with phospholipids and proteins, is important in the maintenance of normal cellular membrane fluidity. At physiological temperatures, the cholesterol molecule interacts with the fatty acids of the membrane phospholipids and causes increased packing of the lipid molecules and hence a reduction of membrane fluidity. Thus, all vertebrate cells require cholesterol in their membranes in order for the cell to function normally. Cholesterol is also important as a precursor for a number of other essential compounds, including steroid hormones, bile acids, and vitamin D. See also Steroid.

Cellular cholesterol is obtained both from the diet, following its absorption in the intestine, and from synthesis within all cells of the body. Foods that are particularly high in cholesterol include eggs, red meat, and organs such as liver and brain. About 40–50% of the dietary cholesterol is absorbed from the intestine per day. In contrast, plant sterols are very poorly absorbed. Cholesterol synthesis occurs in all vertebrate cells but is highest in the liver, intestine, and skin, and in the brain at the time of myelination.

Cholesterol and cholesteryl esters are essentially insoluble in water. In order to transport these compounds around the body in the blood, the liver and intestine produce various lipid-protein complexes, called lipoproteins, which serve to solubilize them. Lipoproteins are large, complex mixtures of cholesterol, cholesteryl esters, phospholipids, triglycerides (fats), and various proteins. The major lipoproteins include chylomicrons, very low density lipoprotein (VLDL), low-density lipoprotein, and high-density lipoprotein (HDL).

Total plasma cholesterol levels of less than 200 mg/100 ml are considered desirable. Values of 200–239 or greater than 239 mg per 100 ml are considered, respectively, borderline high or high risk values, indicating the potential for a heart attack. High levels of low-density lipoprotein in the plasma are associated with increased risk of atherosclerosis, (“hardening of the arteries”), which involves deposition of cholesterol and other lipids in the artery wall. Diets low in cholesterol and saturated fats often result in a reduction in total plasma and LDL cholesterol levels. Such changes in blood cholesterol levels are thought to be beneficial and to reduce the incidence of heart attacks.

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.

The principal sterol in animal tissues, an essential component of cell membranes and the precursor for the formation of the steroid hormones. It is transported in the plasma lipoproteins. Not a dietary essential, since it is synthesized in the body. Eggs contain about 450 mg, milk 14 mg, cheese 70-120 mg, brain 2.2 mg, liver and kidney 300-600 mg, poultry 70-100 mg, and fish 50-60  mg/100 g.

An elevated plasma concentration of cholesterol is a risk factor for atherosclerosis. The synthesis of cholesterol in the body is increased by a high intake of saturated fats, but apart from people with a rare genetic defect in the regulation of cholesterol synthesis, dietary intake of cholesterol does not affect the plasma concentration very much, since there is normally strict control over the rate of synthesis. See also hypercholesterolaemia; hyperlipidaemia; HMG CoA reductase inhibitors; lipids, plasma.

A white, waxy substance, related to fats. It occurs naturally in most animal tissue. Foods particularly rich in cholesterol include eggs and offal.

Many people are surprised to learn that cholesterol has a number of essential functions in the human body: it is used in tissue repair; for strengthening cell membranes; and for the manufacture of bile salts, steroid hormones (including the sex hormones, oestrogen and testosterone), and vitamin D. There is little danger of cholesterol deficiency because it can be manufactured in the liver from fats, carbohydrates, and proteins.

The problems associated with cholesterol arise because modern diets in northern Europe and North America often result in over-production. A lot of cholesterol is not used but is deposited in the walls of blood vessels where it increases the risk of coronary heart disease and atherosclerosis. The most influential factor in raising blood cholesterol levels is eating foods high in saturated fat. Nicotine increases deposition of cholesterol in the walls of blood vessels. Hereditary factors are also important determinants of blood cholesterol levels.

A good diet can decrease blood cholesterol levels. Soluble fibre, polyunsaturated fat (especially fish fats which contain omega-3 fatty acids), and monounsaturated fat (such as olive oil) may all lower cholesterol levels. Regular aerobic exercise helps to reduce deposition of cholesterol in blood vessels.

Blood cholesterol levels vary considerably and there is no universally accepted safe level, but the following are guidelines used by most doctors:

A lipid common to all animal, but not plant, cells. As a sterol, it contains the cyclopentanophenanthrene nucleus. High levels are found in nerve tissue, atheromas, gallstones, and cysts. Normally 140 to 220 mg are present in 100 ml of blood.

Definition

Cholesterol is a fatty substance found in animal tissue and is an important component to the human body. It is manufactured in the liver and carried throughout the body in the bloodstream. Problems can occur when too much cholesterol forms an accumulation of plaque on blood vessel walls, which impedes blood flow to the heart and other organs. The highest cholesterol content is found in meat, poultry, shellfish, and dairy products.

Description

Cholesterol is the Dr. Jekyll and Mr. Hyde of medicine, since it has both a good side and bad side. It is necessary to digest fats from food, make hormones, build cell walls, and participate in other processes for maintaining a healthy body. When people talk about cholesterol as a medical problem, they are usually referring to high cholesterol. This can be somewhat misleading, since there are four components to cholesterol. These are:

• LDL, the so-called bad cholesterol
• HDL, the so-called good cholesterol
• triglycerides, a blood fat lipid that increases the risk for heart disease
• total cholesterol

The U.S. Food and Drug Administration (FDA) estimates that 90 million American adults, roughly one-half of the adult population, have elevated cholesterol levels. High LDL (low-density lipoprotein) is a major contributing factor of heart disease. The cholesterol forms plaque in the heart's blood vessels, which restricts or blocks the supply of blood to the heart, and causes a condition called atherosclerosis. This can lead to a heart attack, resulting in damage to the heart and possibly death.

In 2001, chemical researchers found a link between cholesterol and Alzheimer's disease. Reducing the amount of cholesterol in the cells appears to block attachment of senile plaques to the brain's neurons. (The plaques begin the process that eventually kills brain neurons.) More study remains to test the effects of cholesterol on Alzheimer's.

The population as a whole is at some risk of developing high LDL cholesterol in their lifetimes. Specific risk factors include a family history of high cholesterol, obesity, heart attack or stroke, alcoholism, and lack of regular exercise. The chances of developing high cholesterol increase after the age of 45. One of the primary causes of high LDL cholesterol is too much fat or sugar in the diet, a problem especially true in the United States. Cholesterol also is produced naturally in the liver and overproduction may occur even in people who limit their intake of high cholesterol food. Low HDL and high triglyceride levels also are risk factors for atherosclerosis.

Causes & Symptoms

There are no readily apparent symptoms that indicate high LDL or triglycerides, or low HDL. The only way to diagnose a problem is through a simple blood test. However, one general indication of high cholesterol is obesity. Another is a high-fat diet. In 2001, new research involving twins demonstrated that both genetic factors and diet contribute to cholesterol levels.

Diagnosis

High cholesterol often is diagnosed and treated by general practitioners or family practice physicians. In some cases, the condition is treated by an endocrinologist or cardiologist. Total cholesterol, LDL, HDL, and triglyceride levels as well as the cholesterol to HDL ratio are measured by a blood test called a lipid panel. The cost of a lipid panel is generally $40-100 and is covered by most health insurance and HMO plans, including Medicare, providing there is an appropriate reason for the test. Home cholesterol testing kits are available over the counter but test only for total cholesterol. The results should only be used as a guide and if the total cholesterol level is high or low, a lipid panel should be performed by a physician. In most adults the recommended levels, measured by milligrams per deciliter (mg/dL) of blood, are: total cholesterol, less than 200; LDL, less than 130; HDL, more than 35; triglycerides, 30-200; and cholesterol to HDL ratio, four to one. However, the recommended cholesterol levels may vary, depending on other risk factors such as hypertension, a family history of heart disease, diabetes, age, alcoholism, and smoking.

Doctors have always been puzzled by why some people develop heart disease while others with identical HDL and LDL levels do not. New studies indicate it may be due to the size of the cholesterol particles in the

bloodstream. A test called a nuclear magnetic resonance (NMR) LipoProfile exposes a blood sample to a magnetic field to determine the size of the cholesterol particles. Particle size also can be determined by a centrifugation test, where blood samples are spun very quickly to allow particles to separate and move at different distances. The smaller the particles, the greater the chance of developing heart disease. It allows physicians to treat patients who have normal or close to normal results from a lipid panel but abnormal particle size.

Treatment

The primary goal of cholesterol treatment is to lower LDL to under 160 mg/dL in people without heart disease and who are at lower risk of developing it. The goal in people with higher risk factors for heart disease is less than 130 mg/dL. In patients who already have heart disease, the goal is under 100 mg/dL, according to FDA guidelines. Also, since low HDL levels increase the risks of heart disease, the goal of all patients is more than 35 mg/dL.

In both alternative and conventional treatment of high cholesterol, the first-line treatment options are exercise, diet, weight loss, and stopping smoking. Other alternative treatments include high doses of niacin, soy protein, garlic, algae, and the Chinese medicine supplement Cholestin (a red yeast fermented with rice).

Diet and Exercise

Since a large number of people with high cholesterol are overweight, a healthy diet and regular exercise are probably the most beneficial natural ways to control cholesterol levels. In general, the goal is to substantially reduce or eliminate foods high in animal fat. These include meat, shellfish, eggs, and dairy products. Several specific diet options are beneficial. One is the vegetarian diet. Vegetarians typically get up to 100% more fiber and up to 50% less cholesterol from food than non-vegetarians. The vegetarian low-cholesterol diet consists of at least six servings of whole grain foods, three or more servings of green leafy vegetables, two to four servings of fruit, two to four servings of legumes, and one or two servings of non-fat dairy products daily.

A second diet is the Asian diet, with brown rice being the staple. Other allowable foods include fish, vegetables such as bok choy, bean sprouts, and black beans. It allows for one weekly serving of meat and very few dairy products. The food is flavored with traditional Asian spices and condiments, such as ginger, chilies, turmeric, and soy sauce.

Another regimen is the low glycemic or diabetic diet, which can raise the HDL (good cholesterol) level by as much as 20% in three weeks. Low glycemic foods promote a slow but steady rise in blood sugar levels following a meal, which increases the level of HDL. They also lower total cholesterol and triglycerides. Low glycemic foods include certain fruits, vegetables, beans, and whole grains. Processed and refined foods and sugars should be avoided.

Exercise is an extremely important part of lowering bad cholesterol and raising good cholesterol. It should consist of 20-30 minutes of vigorous aerobic exercise at least three times a week. Exercises that cause the heart to beat faster include fast walking, bicycling, jogging, roller skating, swimming, and walking up stairs. There also are a wide selection of aerobic programs available at gyms or on videocassette.

Garlic

A number of clinical studies have indicated that garlic can offer modest reductions in cholesterol. A 1997 study by nutrition researchers at Pennsylvania State University found men who took garlic capsules for five months reduced their total cholesterol by 7% and LDL by 12%. Another study showed that seven cloves of fresh garlic a day significantly reduced LDL, as did a daily dose of four garlic extract pills. Other studies in 1997 and 1998 back up these results. However, two more recent studies have questioned the effectiveness of garlic in lowering "bad cholesterol."

Cholestin

Cholestin hit the over-the-counter market in 1997 as a cholesterol-lowering dietary supplement. It is a processed form of red yeast fermented with rice, a traditional herbal remedy used for centuries by the Chinese. Two studies released in 1998 showed Cholestin lowered LDL cholesterol by 20-30%%. It also appeared to raise HDL and lower triglyceride levels. Although the supplement contains hundreds of compounds, the major active LDL-lowering ingredient is lovastatin, a chemical also found in the prescription drug Mevacor. The FDA banned Cholestin in early 1998 but a federal district court judge lifted the ban a year later, ruling the product was a dietary supplement, not a drug. It is not fully understood how the substance works and patients may want to consult with their physician before taking Cholestin. No serious side effects have been reported, but minor side effects, including bloating and heartburn, have been reported.

Other Treatments

A study released in 1999 indicated that blue-green algae contains polyunsaturated fatty acids that lower cholesterol. The algae, known as alga Aphanizomenon flosaquae (AFA) is available as an over-the-counter dietary supplement. Niacin, also known as nicotinic acid or vitamin B₃, has been shown to reduce LDL levels by 10-20%, and raise HDL levels by 15-35%. It also can reduce triglycerides. But because an extremely high dose of niacin (2-3 grams) is needed to treat cholesterol problems, it should only be taken under a doctor's supervision to monitor possible toxic side effects. Niacin also can cause flushing when taken in high doses. Soy protein with high levels of isoflavones also have been shown to reduce bad cholesterol by up to 10%. A daily diet that contains 62 mg of isoflavones in soy protein is recommended, and can be incorporated into other diet regimens, including vegetarian, Asian, and low glycemic. In 2003, research revealed that policosanol, a substance made from sugar cane wax or beeswax, lowered LDL cholesterol nearly 27% in study subjects in a Cuban study.

Allopathic Treatment

A wide variety of prescription medicines are available to treat cholesterol problems. These include statins such as Mevacor (lovastatin), Lescol (fluvastatin), Pravachol (pravastatin), Zocor (simvastatin), Baycol (cervastatin), and Lipitor (atorvastatin) to lower LDL. A group of drugs called fibric acid derivatives are used to lower triglycerides and raise HDL. These include Lopid (gemfibrozil), Atromid-S (clofibrate), and Tricor (fenofibrate).

A new class of drugs was identified late in 2001 that work differently from the statin drugs. These drugs rely on compounds that bind to a sterol that regulates protein (called SCAP) and speds up removal of cholesterol from the plasma (the fluid part of the blood.) Doctors decide which drug to use based on the severity of the cholesterol problem, side effects, and cost.

Expected Results

High cholesterol is one of the key risk factors for heart disease. Left untreated, too much bad cholesterol can clog the blood vessels, leading to chest pain (angina), blood clots, and heart attacks. Heart disease is the number one killer of men and women in the United States. By reducing LDL, people with heart disease may prevent further heart attacks and strokes, prolong and improve the quality of their lives, and slow or reverse cholesterol buildup in the arteries. In people without heart disease, lowering LDL can decrease the risk of a first heart attack or stroke.

Prevention

The best way to prevent cholesterol problems is through a combination of healthy lifestyle activities, a primarily low-fat and high-fiber diet, regular aerobic exercise, not smoking, and maintaining an optimal weight. In a small 2003 Canadian study, people who ate a low-fat vegetarian diet consisting of foods that are found to help lower cholesterol dropped their levels of LDL cholesterol as much as results from some statin drugs. But for people with high risk factors for heart disease, such as a family history of heart disease, diabetes, and being over the age of 45, these measures may not be enough to prevent the onset of high cholesterol. There are studies being done on the effectiveness of some existing anti-cholesterol drugs for controlling cholesterol levels in patients who do not meet the criteria for high cholesterol but no definitive results are available.

Resources

Books

Bratman, Steven and David Kroll. Natural Pharmacist: Natural Treatments for High Cholesterol. Roseville, CA: Prima Publishing, 2000.

Ingels, Darin. The Natural Pharmacist: Your Complete Guide to Garlic and Cholesterol. Roseville, CA: Prima Publishing, 1999.

Murray, Michael T. Natural Alternatives to Over-the-Counter and Prescription Drugs New York: William Morrow & Co., 1999.

Trubo, Richard. Cholesterol Cures: From Almonds and Antioxidants to Garlic, Golf, Wine and Yogurt. Emmaus, PA: Rodale Press, 1996.

Periodicals

"Both Genetics and Diet Influence Cholesterol Levels." Heart Disease Weekly (October 14, 2001).

Carter, Ann. "Cholesterol in Your Diet." Clinical Reference Systems (July 1, 1999): 282.

"Chemical Engineers Suggest Alzheimer Onset Tied to Cholesterol." Pain and Central Nervous System Week (December 24, 2001):3.

"Eating a Vegetarian Diet that Includes Cholesterol-lowering Foods may Lower Lipid Levels as Much as Some Medications." Environmental Nutrition (March 2003):8.

"Researchers Identify New Class of Cholesterol-Lowering Drugs." Heart Disease Weekly (December 23, 2001):14.

Sage, Katie. "Cut Cholesterol with Policosanol: This Supplement Worked Better than a Low-fat Diet in One Study." Natural Health (March 2003):32.

Marandino, Cristin. "The Case for Cholesterol." Vegetarian Times (August 1999): 10.

Schmitt, B.D. "Treating High Cholesterol Levels." Clinical Reference Systems (July 1, 1999): 1551.

VanTyne, Julia, and Davis, Lori. "Drop Your Cholesterol 25 to 100 Points." Prevention (November 1999): 110.

Organizations

National Cholesterol Education Program. NHLBI Information Center, P.O. Box 30105, Bethesda, MD 20824-0105. http://www.nhlbi.nih.gov.

[Article by: Ken R. Wells; Teresa G. Odle]

A lipid-related compound found in tissues and manufactured in the liver. Cholesterol has a number of essential functions: it is important for body tissue repair; it is a constituent of cell membranes which it helps strengthen; it forms the starting point of steroid manufacture and is involved in the formation of several hormones; it forms bile salts; and it is the raw material for vitamin D. Dietary sources of cholesterol include animal products such as eggs, meat, and cheese. A high-fat diet can increase blood cholesterol levels. Nicotine (from tobacco smoking) increases deposition of cholesterol in arterial walls, but hereditary factors are also important determinants of blood cholesterol levels. High blood cholesterol levels are associated with cardiovascular diseases. Blood cholesterol levels can be decreased by taking regular aerobic exercise and eating a low-fat diet. A deficiency of cholesterol is rare. See also high-density lipoproteins, low-density lipoproteins.

Cholesterol is one of the most widely disseminated organic compounds in the animal kingdom. Almost three hundred years ago, Antonio Vallisnieri observed that gallstones were soluble in turpentine or alcohol. Poulletier de la Salle, some thirty years later, demonstrated that the main constituent of gallstones could be crystallized from alcohol. This substance was thought to be a wax until 1815, when Michel Eugène Chevreul showed that it was not saponifiable and gave it the name "cholesterine" derived from the Greek chole, bile, and steros, solid. Soon thereafter, it was isolated from blood, brain, tumors, and egg yolk. The isolated compounds were shown to be identical. In 1843 Vogel found it in atherosclerotic arteries.

The chemical structure of cholesterol was elucidated over the years beginning in 1859. The compound was shown to contain a secondary hydroxyl group and a double bond. The exact empirical formula (C₂₇H₄₆O) was established in 1888 by Friedrich Reinitzer. Proof of structure was obtained chiefly through the brilliant work of Adolf Windaus and Heinrich Wieland. The structure of cholesterol suggested by Windaus and Wieland in the 1920s was incorrect, but that does not detract in any way from their contribution. The true structure was established in the 1930s based on X-ray diffraction data.

There were many suggestions regarding the biological synthesis of cholesterol. The biosynthetic pathway became accessible with the introduction of radioactive carbon in the 1940s. The biosynthetic scheme was generally elucidated by the work of Konrad Bloch, George Popjak, and John Cornforth. It was first shown that cholesterol could be synthesized in mammals and ergosterol in yeast from small organic molecules. Eventually it was shown that all twenty-seven carbon atoms of cholesterol were derived from the two carbon atoms of acetate. The methyl group of acetate contributed fifteen of the twenty-seven carbons of cholesterol and the carboxyl group contributed twelve. The pathway began with the condensation of two acetate residues to give acetoacetate and addition of one more two-carbon moiety to yield hydroxymethylglutaric acid (HMG). HMG lost a carbon atom and the resulting compound rearranged to provide an isoprene unit. Two five-carbon units combined to give a geranyl derivative that added another isoprene to give a farnesyl unit. Two farnesyl units united to provide squalene (C₃₀H₅₀), a hydrocarbon found in the livers of some species of shark that cyclyzed to yield lanosterol, a thirty-carbon atom sterol also found in sheep wool. In a series of rearrangements and demethylations, lanosterol yielded cholesterol. The key step in this complex synthetic pathway involves the reduction of HMG-CoA. Inhibition of HMG-CoA reductase is the basis of a number of potent new serum cholesterol-lowering drugs.

Cholesterol represents about 0.2 percent of the weight of the human body. As Table 1 shows, the bulk of the body's cholesterol is present in two tissues; one is the brain and nerve tissue, the other is muscle. In the brain, cholesterol is thought to act as an insulator, but there have been relatively few studies of the metabolism of brain cholesterol. The next large reservoir of cholesterol is muscle. Between them, nervous tissue and muscle carry 44 percent of the body's cholesterol. The cholesterol in these reservoirs turns over slowly.

Cholesterol is ubiquitous in the human body, where it plays structural and metabolic roles. Together with phospholipid, cholesterol is present in every cell membrane. In the adrenals, cholesterol is converted to adrenocortical hormones such as cortisone. In the gonads, cholesterol is converted to the appropriate sex hormone—estradiol in women, testosterone in men. The cholesterol in skin is the precursor of 7-dehydrocholesterol, which is ultimately converted to vitamin D. The major catabolic products of cholesterol are the bile acids—cholic and chenodeoxycholic. These are designated as the primary bile acids; they are metabolized in the liver to deoxycholic and lithocholic acids. It has been estimated that over 90 percent of biologically synthesized cholesterol is metabolized to bile acids. In general, the body synthesizes more cholesterol than it ingests.

Table 1

In 1912 Nicolai Anitschkow showed that cholesterolfed rabbits developed aortic deposits similar to early human atherosclerosis. His experiments presented a possible explanation of human atherosclerosis and that particular debate has not yet abated. Simultaneously with Anitschkow's studies, A. I. Ignatowski demonstrated the atherogenic potential of animal protein, but compared to work on cholesterol and fat there has only been a desultory interest in protein effects.

Since Anitschkow's results were obtained by dietary manipulation, the view that dietary cholesterol was implicated in atherogenesis was accepted generally. With development of simple, rapid methods of cholesterol analysis, it became possible to screen populations for blood cholesterol content. Large epidemiological studies were launched and their results helped to develop the concept of risk factors for heart disease. Currently, the major risk factors are hypercholesterolemia, hypertension, smoking, obesity, and maleness. However, emerging data suggest that homocysteinemia and inflammation (due to infection with cytomegalovirus or chlamydia pneumoniae) are also important factors.

When cholesterol is ingested, it is emulsified with phospholipid and absorbed. The absorbed lipid circulates in the blood as a water soluble lipid-protein complex called lipoprotein. Initially, absorbed cholesterol is part of a large, triglyceride-rich particle called the chylomicron. In the course of circulation, the triglyceride is removed by activity of cellular lipases and the particles become smaller and their cholesterol content increases. The cholesterol-containing, lipid-protein complex consists of several fractions that are separable by virtue of their hydrated densities. In general terms, the four major fractions are the triglyceride-rich chylomicrons and very low density (VLDL), the cholesterol-rich low density (LDL), and the protein-rich high density (HDL).

Due to development by John Gofman of methods for ultracentrifugal separation of lipoproteins, researchers have been able to isolate and study lipoproteins. The cholesterol-rich low density lipoproteins (LDL) are thought to be major risk factors for coronary disease. It was demonstrated that oxidized LDL is the real villain in coronary disease. It also was shown that LDL can be subfractionated into small, dense and large "fluffy" particles. The small particles appear to infiltrate the artery preferentially. Researchers also know that the process of atherogenesis is not simple and is mediated by an array of small proteins. The high-density lipoproteins are about 50 percent protein. In the simplest terms, LDL facilitates entry of cholesterol into cells and HDL facilitates its removal. LDL receptors on the cell surface facilitate LDL uptake. The proteins of lipoproteins are very important because they provide recognition by cells, and it is now becoming evident that genetic differences in apolipoproteins may dictate susceptibility to disease as well as chances for the efficacy of medication.

The effects of dietary cholesterol became a concern shortly after Anitschkow's observation and warnings regarding excess levels of cholesterol intake, which constitute one of the foundations of dietary therapy. Since cholesterol occurs only in food of animal origin, it was a simple extension to seek an explanation of the role of cholesterol by examining the lipids of food from animal sources. Although no dietary fat is totally saturated or unsaturated, attention also turned to effects of fat saturation.

The amount of cholesterol in the average American diet is in the range of 300–350 mg/day. It used to be much higher. The levels of cholesterol in a number of common animal foods are given in Table 2. It is evident that most muscle contains about the same amount of cholesterol, 81 ± 7 mg/100g. Cholesterol content of butter (per 100 g) is high, but we rarely eat more than 5–10 g of butter per meal. Shrimp is high in cholesterol but very low in fat. Eggs are also high in cholesterol. Continuing research nevertheless indicates that the cholesterol level of a food per se has little effect on serum cholesterol levels. The cholesterolemic effect is a function of dietary fat saturation. It has been shown that the absorption of cholesterol is more a function of the accompanying dietary fat than of cholesterol itself. Saturated dietary fat leads to higher cholesterol levels than does unsaturated fat. This observation is true for most people who are called "non-responders" (to dietary cholesterol). A small number of people are "responders," meaning they absorb more cholesterol, regardless of accompanying fat. In the late 1960s, Keys and Hegsted developed formulas for estimating changes in serum cholesterol based upon changes in dietary fat. There have been a number of more complex formulas developed, but the originals are referred to most often today. Essentially, they found saturated fatty acids to be hypercholesterolemic and unsaturated fatty acids to lower cholesterol. Stearic acid was considered neutral. The polyunsaturated fats lower cholesterol across the board so that HDL cholesterol (the "good" cholesterol) falls as does LDL cholesterol. Oleic acid seems to affect only LDL cholesterol. The reduction in total cholesterol may not be as profound, but the LDL/HDL cholesterol ratio is improved. Recent findings show that the structure of individual triglycerides may also influence their atherogenicity.

In summary, cholesterol is a substance that appears in all cells and also has a number of metabolic functions.

Table 2

It is synthesized in the body and is part of every cell membrane. Cholesterol is metabolized to adrenocortical or sex hormones, bile acids, and vitamin D. Levels of serum cholesterol are related to risk of coronary disease, but it should be borne in mind that cardiovascular disease is a metabolic disease, not one of cholesterol deposition. Dietary cholesterol is absorbed, but its effects on serum cholesterol are slight. Generally, there is an increase of about 2 mg of serum cholesterol for every 100 mg ingested. Cholesterol should be viewed as a chemical necessary for life and not as a toxic substance. As with so many other aspects of life, moderation is the key.

Bibliography

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Howell, Wanda H., et al. "Plasma Lipid and Lipoprotein Responses to Dietary Fat and Cholesterol: A Meta Analysis." American Journal of Clinical Nutrition 65 (1997): 1747–1764.

Keys, Ancel, Joseph T. Anderson, and Francisco Grande. "Serum Cholesterol Response to Changes in Diet, IV: Particular Fatty Acids in the Diet." Metabolism 14 (1965): 776–787.

Kritchevsky, David. Cholesterol. New York: Wiley, 1958.

Kritchevsky, David. "Food Lipids and Atherosclerosis." In Food Lipids and Health, edited by Richard E. McDonald and David B. Min. New York: M. Dekker, 1996.

Leinoneu, M. "Chlamydia pneumoniae and Other Risk Factors for Atherosclerosis." Journal of Infectious Diseases 181, Suppl. 3 (2000): S414–S416.

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Myant, Nick B. Cholesterol Metabolism, LDL, and the LDL Receptor. San Diego, Calif.: Academic Press, Inc., 1990.

—David Kritchevsky

A white soapy substance found in the tissues of the body and in certain foods, such as animal fats, oils, and egg yolks. Cholesterol has been linked to heart disease and atherosclerosis. (It collects on the walls of arteries and interferes with the flow of blood.) High levels of cholesterol in the blood are considered to be unhealthy. (See saturated fats, HDL, and LDL.)

A steroid alcohol found in animal fats and oils, bile, blood, brain tissue, milk, egg yolk, myelin sheaths of nerve fibers, liver, kidneys and adrenal glands. It is a necessary component of all cell surface and intracellular membranes and a constituent of myelin in nervous tissue; it is a precursor of bile acids and steroid hormones, and it occurs in the most common type of gallstone, in atheroma of the arteries, in various cysts, and in carcinomatous tissue. Most of the body's cholesterol is synthesized, but some is obtained in the diet.
The preoccupation in human medicine with the relationship between cholesterol and the development of atheromatous plaques in the coronary arteries is not reflected in veterinary medicine. The importance of cholesterol to the veterinarian is limited to the measurement of blood cholesterol levels as an indicator of liver disease or thyroid activity.

• c. pneumonia — see endogenous-lipid pneumonia.

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Cholesterol
IUPAC name (3β)-​cholest-​5-​en-​3-​ol
other names (10R,​13R)-​10,​13-​dimethyl-​17-​(6-​methylheptan-​2-​yl)-​2,​3,​4,​7,​8,​9,​11,​12,​14,​15,​16,​17-​dodecahydro-​1H-​cyclopenta​[a]phenanthren-​3-​ol
Identifiers
CAS number	57-88-5 Y
PubChem	5997
ChemSpider	5775
SMILES	O[C@@H]4C/C3=C/C[C@@H]1[C@H](CC[C@]2([C@H]1CC[C@@H]2[C@H](C)CCCC(C)C)C)[C@@]3(C)CC4
InChI	1/C27H46O/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28)13-15-26(20,4)25(22)14-16-27(23,24)5/h9,18-19,21-25,28H,6-8,10-17H2,1-5H3/t19-,21+,22+,23-,24+,25+,26+,27-/m1/s1
InChI key	HVYWMOMLDIMFJA-DPAQBDIFBB
Properties
Molecular formula	C27H46O
Molar mass	386.65 g/mol
Appearance	white crystalline powder[1]
Density	1.052 g/cm3
Melting point	148–150 °C[1]
Boiling point	360 °C (decomposes)
Solubility in water	0.095 mg/L (30 °C)
Solubility	soluble in acetone, benzene, chloroform, ethanol, ether, hexane, isopropyl myristate, methanol
Y (what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Microscopic appearance of cholesterol crystals in water. Photo taken under polarized light.

Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals.^[2] It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile acids, steroid hormones, and several fat-soluble vitamins. Cholesterol is the principal sterol synthesized by animals, but small quantities are synthesized in other eukaryotes, such as plants and fungi. It is almost completely absent among prokaryotes, which include bacteria.^[3]

The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as François Poulletier de la Salle first identified cholesterol in solid form in gallstones, in 1769. However, it was only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".^[4]

Contents 1 Physiology 1.1 Overview 1.2 Function 1.3 Dietary sources 1.4 Synthesis 1.5 Regulation of cholesterol synthesis 1.6 Plasma transport and regulation of absorption 1.7 Metabolism, recycling and excretion 2 Clinical significance 2.1 Hypercholesterolemia 2.2 Hypocholesterolemia 2.3 Cholesterol testing 3 Cholesteric liquid crystals 4 See also 5 Additional images 6 References 7 External links

Physiology

Overview

Since cholesterol is essential for all animal life, it is primarily synthesized from simpler substances within the body. However, high levels in blood circulation, depending on how it is transported within lipoproteins, are strongly associated with progression of atherosclerosis. For a person of about 68 kg (150 pounds), typical total body cholesterol synthesis is about 1 g (1,000 mg) per day, and total body content is about 35 g. Typical daily additional dietary intake, in the United States and societies with similar dietary patterns, is 200–300 mg. The body compensates for cholesterol intake by reducing the amount synthesized.

Cholesterol is recycled. It is excreted by the liver via the bile into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream. Intestinal tract absorption is highly selective for cholesterol, excreting plant stanols and sterols (which promote atherosclerosis progression more than cholesterol), back into the intestinal lumen for elimination.

Function

Cholesterol is required to build and maintain membranes; it regulates membrane fluidity over the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty acid chain of the other lipids. In this structural role, cholesterol reduces the permeability of the plasma membrane to protons (positive hydrogen ions) and sodium ions.^[5]

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis. The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane. In many neurons, a myelin sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.^[6]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in the gallbladder. Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, Vitamin A, Vitamin D, Vitamin E, and Vitamin K. Cholesterol is an important precursor molecule for the synthesis of Vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.

Some research indicates that cholesterol may act as an antioxidant.^[7]

Dietary sources

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat contain cholesterol to varying extents.^[8] Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp.^[9] Human breast milk also contains significant quantities of cholesterol.^[10] Cholesterol is not present in plant-based food sources unless it has been added during the food's preparation.^[9] However, plant products such as flax seeds and peanuts contain cholesterol-like compounds called phytosterols, which are suggested to help lower serum cholesterol levels.^[11]

Total fat intake, especially saturated fat and trans fat^[12], plays a larger role in blood cholesterol than intake of cholesterol itself. Saturated fat is present in full fat dairy products, animal fats, several types of oil and chocolate. Trans fats are typically derived from the partial hydrogenation of unsaturated fats, and, in contrast to other types of fat, do not occur in significant amounts in nature. Research supports a recommendation to minimize or eliminate trans fats from the diet due to their adverse health effects.^[13] Trans fat is most often encountered in margarine and hydrogenated vegetable fat, and consequently in many fast foods, snack foods, and fried or baked goods.

A change in diet in addition to other lifestyle modifications may help reduce blood cholesterol. Avoiding animal products may decrease the cholesterol levels in the body not through dietary cholesterol reduction alone but primarily through a reduced saturated fat intake. Those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily calories from saturated fat and less than 200 mg of cholesterol per day.^[14]

The view that a change in diet (to be specific, a reduction in dietary fat and cholesterol) can lower blood cholesterol levels, and thus reduce the likelihood of development of, among others, coronary artery disease (CHD) has been challenged. An alternative view is that any reductions to dietary cholesterol intake are counteracted by the organs such as the liver, which will increase or decrease production of cholesterol to keep blood cholesterol levels constant.^[15]

Synthesis

About 20–25% of total daily cholesterol production occurs in the liver; other sites of high synthesis rates include the intestines, adrenal glands, and reproductive organs. Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step is an irreversible step in cholesterol synthesis and is the site of action for the statins (HMG-CoA Reductase Inhibitors).

Mevalonate is then converted to 3-isopentenyl pyrophosphate in three reactions that require ATP. This molecule is decarboxylated to isopentenyl pyrophosphate, which is a key metabolite for various biological reactions. Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally, lanosterol is then converted to cholesterol.^[16]

Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of cholesterol and fatty acid metabolism.

Regulation of cholesterol synthesis

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, whereas lower intake from food has the opposite effect. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).^[17] In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage-activating protein) and Insig1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex, allowing the complex to migrate to the Golgi apparatus, where SREBP is cleaved by S1P and S2P (site-1 and -2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the SRE (sterol regulatory element), which stimulates the transcription of many genes. Among these are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol.^[18] A large part of this signaling pathway was clarified by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in the 1970s. In 1985, they received the Nobel Prize in Physiology or Medicine for their work. Their subsequent work shows how the SREBP pathway regulates expression of many genes that control lipid formation and metabolism and body fuel allocation.

Cholesterol synthesis can be turned off when cholesterol levels are high, as well. HMG CoA reductase contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain. The membrane domain functions to sense signals for its degradation. Increasing concentrations of cholesterol (and other sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteosome. This enzyme's activity can also be reduced by phosphorylation by an AMP-activated protein kinase. Because this kinase is activated by AMP, which is produced when ATP is hydrolyzed, it follows that cholesterol synthesis is halted when ATP levels are low.^[19]

Plasma transport and regulation of absorption

See also: Blood lipids

Cholesterol is only slightly soluble in water; it can dissolve and travel in the water-based bloodstream at exceedingly small concentrations. Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exterior composed of amphiphilic proteins and lipids whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble; triglycerides and cholesterol esters are carried internally. Phospholipids and cholesterol, being amphipathic, are transported in the surface monolayer of the lipoprotein particle.

In addition to providing a soluble means for transporting cholesterol through the blood, lipoproteins have cell-targeting signals that direct the lipids they carry to certain tissues. For this reason, there are several types of lipoproteins within blood called, in order of increasing density, chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The more cholesterol and less protein a lipoprotein has the less dense it is. The cholesterol within all the various lipoproteins is identical, although some cholesterol is carried as the "free" alcohol and some is carried as fatty acyl esters referred to as cholesterol esters. However, the different lipoproteins contain apolipoproteins, which serve as ligands for specific receptors on cell membranes. In this way, the lipoprotein particles are molecular addresses that determine the start- and endpoints for cholesterol transport.

Chylomicrons, the least dense type of cholesterol transport molecules, contain apolipoprotein B-48, apolipoprotein C, and apolipoprotein E in their shells. Chylomicrons are the transporters that carry fats from the intestine to muscle and other tissues that need fatty acids for energy or fat production. Cholesterol, which is not used by muscles, remains in more cholesterol-rich chylomicron remnants, which are taken up from the bloodstream by the liver.

VLDL molecules are produced by the liver and contain excess triacylglycerol and cholesterol that is not required by the liver for synthesis of bile acids. These molecules contain apolipoprotein B100 and apolipoprotein E in their shell. During transport in the bloodstream, the blood vessels cleave and absorb more triacylglycerol to leave IDL molecules, which contain an even higher percentage of cholesterol. The IDL molecules have two possible fates: Half are taken up by the liver for metabolism into other biomolecules and the other half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, which have the highest percentage of cholesterol within them.

LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester. The shell of the LDL molecule contains just one molecule of apolipoprotein B100, which is recognized by the LDL receptor in peripheral tissues. Upon binding of apolipoprotein B100, many LDL receptors become localized in clathrin-coated pits. Both the LDL and its receptor are internalized by endocytosis to form a vesicle within the cell. The vesicle then fuses with a lysosome, which has an enzyme called lysosomal acid lipase that hydrolyzes the cholesterol esters. Now within the cell, the cholesterol can be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with cell membranes.

Synthesis of the LDL receptor is regulated by SREBP, the same regulatory protein as was used to control synthesis of cholesterol de novo in response to cholesterol presence in the cell. When the cell has abundant cholesterol, LDL receptor synthesis is blocked so that new cholesterol in the form of LDL molecules cannot be taken up. On the converse, more LDL receptors are made when the cell is deficient in cholesterol. When this system is deregulated, many LDL molecules appear in the blood without receptors on the peripheral tissues. These LDL molecules are oxidized and taken up by macrophages, which become engorged and form foam cells. These cells often become trapped in the walls of blood vessels and contribute to artherosclerotic plaque formation. These plaques are the main causes of heart attacks, strokes, and other serious medical problems, leading to the association of so-called LDL cholesterol (actually a lipoprotein) with "bad" cholesterol.^[19]

Also, HDL particles are thought to transport cholesterol back to the liver for excretion or to other tissues that use cholesterol to synthesize hormones in a process known as reverse cholesterol transport (RCT).^[20] Having large numbers of large HDL particles correlates with better health outcomes.^[21] In contrast, having small numbers of large HDL particles is independently associated with atheromatous disease progression within the arteries.

Metabolism, recycling and excretion

Cholesterol is oxidized by the liver into a variety of bile acids.^[22] These in turn are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and non-conjugated bile acids along with cholesterol itself is excreted from the liver into the bile. Approximately 95% of the bile acids are reabsorbed from the intestines and the remainder lost in the feces.^[23] The excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation which is essential for the digestion and absorption of dietary fats. Under certain circumstances, when more concentrated, as in the gallbladder, cholesterol crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.^[24]

Clinical significance

Hypercholesterolemia

Main articles: hypercholesterolemia and lipid hypothesis

According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia); that is, higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke, and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles,^[25] LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices, and other factors.^[26]

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease. In contrast, HDL particles (especially large HDL) have been identified as a mechanism by which cholesterol and inflammatory mediators can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression. A 2007 study pooling data on almost 900,000 subjects in 61 cohorts demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Still, because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is still larger in older people.^[27]

Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis).^[28] Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. On the converse, the total cholesterol can be within normal limits, yet be made up primarily of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration.^{[citation needed]} Recently, a post-hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol"^[29]

Multiple human trials utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults.^{[citation needed]} As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels,^[30] and in men without cardiovascular disease there is benefit from lowering abnormally high cholesterol levels ("primary prevention").^[31] Primary prevention in women is practiced only by extension of the findings in studies on men,^[32] since in women, none of the large statin trials has shown a reduction in overall mortality or in cardiovascular end points.^[33]

The 1987 report of National Cholesterol Education Program, Adult Treatment Panels suggest the total blood cholesterol level should be: < 200 mg/dL normal blood cholesterol, 200–239 mg/dL borderline-high, > 240 mg/dL high cholesterol.^[34] The American Heart Association provides a similar set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:^[35]

Level mg/dL	Level mmol/L	Interpretation
< 200	< 5.0	Desirable level corresponding to lower risk for heart disease
200–240	5.2–6.2	Borderline high risk
> 240	> 6.2	High risk

However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dL (2.6 mmol/L)^[36], although a newer target of < 70 mg/dL can be considered in higher risk individuals based on some of the above-mentioned trials. A ratio of total cholesterol to HDL—another useful measure—of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dL.^{[citation needed]}

Reference ranges for blood tests, showing usual as well as optimal levels of HDL, LDL and total cholesterol in mass and molar concentrations, found in orange color at right, that is, among the blood constituents with the highest concentration.

Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Usually, only the total, HDL, and triglycerides are measured. For cost reasons, the VLDL is usually estimated as one-fifth of the triglycerides and the LDL is estimated using the Friedewald formula (or a variant): estimated LDL = [total cholesterol] − [total HDL] − [estimated VLDL]. The estimated VLDL and LDL have more error when triglycerides are above 200 mg/dL.^[37] It is important to fast for at least eight hours before the blood test because the triglyceride level varies significantly with food intake.

Given the well-recognized role of cholesterol in cardiovascular disease, it is surprising that some studies have shown an inverse correlation between cholesterol levels and mortality. A 2009 study of patients with acute coronary syndromes found an association of hypercholesterolemia with better mortality outcomes.^[38]. In the Framingham Heart Study, in subjects over 50 years of age they found an 11% increase overall and 14% increase in CVD mortality per 1 mg/dL per year drop in total cholesterol levels. The researchers attributed this phenomenon to the fact that people with severe chronic diseases or cancer tend to have below-normal cholesterol levels.^[39] This explanation is not supported by the Vorarlberg Health Monitoring and Promotion Programme, in which men of all ages and women over 50 with very low cholesterol were increasingly likely to die of cancer, liver diseases, and mental diseases. This result indicates that the low-cholesterol effect occurs even among younger respondents, contradicting the previous assessment among cohorts of older people that this is a proxy or marker for frailty occurring with age.^[40]

A small group of scientists, united in The International Network of Cholesterol Skeptics, continues to question the link between cholesterol and atherosclerosis.^[41] However, the vast majority of doctors and medical scientists accepts the link as fact.^[42]

Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, but some studies suggest a link with depression, cancer, and cerebral hemorrhage. In general, the low cholesterol levels seem to be a consequence of an underlying illness, rather than a cause.^[27]

Cholesterol testing

The examples and perspective in this section report USA measures, whereas the measure in many places is mmol/L, which someone who knows needs to put it, therefore the section may not represent a worldwide view of the subject. Please improve this article and discuss the issue on the talk page. (October 2009)

It is recommended by the American Heart Association to test cholesterol every 5 years for people aged 20 years or older.^[43]

A blood sample after 12-hour fasting is taken by a doctor or a home cholesterol-monitoring device to determine a lipoprotein profile. This measures total cholesterol, LDL (bad) cholesterol, HDL (good) cholesterol, and triglycerides. It is recommended to have cholesterol tested more frequently than 5 years if a person has total cholesterol of 200 mg/dL or more, or if a man over age 45 or a woman over age 50 has HDL (good) cholesterol less than 40 mg/dL, or there exist other risk factors for heart disease and stroke. To convert mg/dl to mmol/L (used in Canada and other parts of the world), divide the mg/dl number by 40.

Cholesteric liquid crystals

Some cholesterol derivatives, (among other simple cholesteric lipids) are known to generate the liquid crystalline cholesteric phase. The cholesteric phase is in fact a chiral nematic phase, and changes colour when its temperature changes. Therefore, cholesterol derivatives are commonly used in liquid crystal thermometers and temperature-sensitive paints.

See also

• Arcus senilis "Cholesterol ring" in the eyes
• Bile salts
• Diet and heart disease
• Lieberman-Burchard test to detect cholesterol
• Niemann Pick disease Type C
• Triglycerides
• Vertical Auto Profile
• oxycholesterol

Additional images

Steroidogenesis, using cholesterol as building material

Space-filling model of the Cholesterol molecule

Numbering of the steroid nuclei

References

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36. ^ "About cholesterol" – American Heart Association
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41. ^ Uffe Ravnskov (2000). The Cholesterol Myths : Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease. New Trends Publishing, Incorporated. ISBN 0-96708-970-0. 
42. ^ Daniel Steinberg (2007). The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. Boston: Academic Press. ISBN 0-12-373979-9. 
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External links

• Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults US National Institutes of Health Adult Treatment Panel III
• Aspects of fat digestion and metabolism – UN/WHO Report 1994
• American Heart Association – "About Cholesterol"

v • d • e Cholestanes, membrane lipids: sterols Adosterol - Cholecalciferol/Ergocalciferols - Cholesterol - Dihydrotachysterol - Fusidic acid - Lanosterol - Phytosterols

v • d • e Cholesterol and steroid metabolic intermediates Mevalonate pathway to HMG-CoA Acetyl-CoA · Acetoacetyl-CoA · HMG-CoA Ketone bodies Acetone · Acetoacetic acid · beta-Hydroxybutyric acid to DMAPP Mevalonic acid · Phosphomevalonic acid · 5-Diphosphomevalonic acid · Isopentenyl pyrophosphate · Dimethylallyl pyrophosphate Geranyl- Geranyl pyrophosphate · Geranylgeranyl pyrophosphate Carotenoid Prephytoene diphosphate · Phytoene Non-mevalonate pathway DOXP · MEP · CDP-ME · CDP-MEP · MEcPP · HMB-PP · IPP · DMAPP To Cholesterol Farnesyl pyrophosphate · Squalene · 2,3-Oxidosqualene · Lanosterol Lanosterol · Lathosterol · 7-Dehydrocholesterol · Cholesterol Lanosterol · Zymosterol · 7-Dehydrodesmosterol · Desmosterol · Cholesterol Steroid Corticosteroids (C21 pregnane) Mineralocorticoids Pregnenolone · Progesterone · 11-Deoxycorticosterone · Corticosterone · Aldosterone Glucocorticoids Pregnenolone · 17-Hydroxypregnenolone · 17-Hydroxyprogesterone · 11-Deoxycortisol · Cortisol Cortisol · Cortisone Sex steroids Androgens (C19 andrane) DHEA · Androstenedione/5-Androstenediol · Testosterone · Dihydrotestosterone DHEA sulfate · Epitestosterone Estrogens (C18 estrane) Estrone · Estradiol · Estriol Nonhuman Phytosterols Stigmasterol · Brassicasterol Ergosterols Ergosterol · Ergocalciferol see also enzymes, disorders Major families of biochemicals Saccharides/Carbohydrates/Glycosides · Amino acids/Peptides/Proteins/Glycoproteins · Lipids/Terpenes/Steroids/Carotenoids · Alkaloids/Nucleobases/Nucleic acids · Cofactors/Phenylpropanoids/Polyketides/Tetrapyrroles

v • d • e Cardiovascular disease: vascular disease · Circulatory system pathology (I70-I99, 440-456) Arteries, arterioles and capillaries Inflammation Arteritis (Aortitis) · Buerger's disease Arterial occlusive disease/ peripheral vascular disease Arteriosclerosis Atherosclerosis (Foam cell, Fatty streak, Atheroma, Intermittent claudication) · Monckeberg's arteriosclerosis · Arteriolosclerosis (Hyaline, Hyperplastic, oxycholesterol, cholesterol, LDL, trans fat) Stenosis Renal artery stenosis · Carotid artery stenosis Other Fibromuscular dysplasia · Degos disease · Aortoiliac occlusive disease · Raynaud's phenomenon/Raynaud's disease · Erythromelalgia Aneurysm/dissection/ pseudoaneurysm torso: Aortic aneurysm (Thoracic aortic aneurysm, Abdominal aortic aneurysm) · Aortic dissection · Coronary artery aneurysm head/neck: Cerebral aneurysm · Intracranial berry aneurysm · Carotid artery dissection · Vertebral artery dissection · Familial aortic dissection Vascular malformation Arteriovenous fistula · Telangiectasia (Hereditary hemorrhagic telangiectasia) Vascular nevus Spider angioma · Halo nevus · Cherry hemangioma Veins Inflammation Phlebitis Venous thrombosis/ Thrombophlebitis primarily lower limb (Deep vein thrombosis) abdomen (May-Thurner syndrome, Portal vein thrombosis, Budd-Chiari syndrome, Renal vein thrombosis) upper limb/torso (Paget-Schroetter disease, Mondor's disease) head (Cerebral venous sinus thrombosis) Post-thrombotic syndrome Varicose veins Varicocele · Gastric varices · Portacaval anastomosis (Hemorrhoid, Esophageal varices, Caput medusae) Other Superior vena cava syndrome · Inferior vena cava syndrome · Venous ulcer · Chronic venous insufficiency · Chronic cerebrospinal venous insufficiency Arteries or veins Vasculitis · Thrombosis · Embolism (Pulmonary embolism, Cholesterol embolism, Paradoxical embolism) · Angiopathy (Macroangiopathy, Microangiopathy) Blood pressure Hypertension Hypertensive heart disease · Hypertensive nephropathy · Essential hypertension  · Secondary hypertension (Renovascular hypertension) · Pulmonary hypertension · Malignant hypertension · Benign hypertension · Systolic hypertension · White coat hypertension Hypotension Orthostatic hypotension vascular navs: anat/physio/dev, noncongen/systemic vasculitis/congen/neoplasia, symptoms+signs/eponymous, proc

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Dansk (Danish)
n. - kolesterol

Nederlands (Dutch)
cholesterol

Français (French)
n. - cholestérol

Deutsch (German)
n. - Cholesterin, Gallenfett

Ελληνική (Greek)
n. - (βιολ.) χοληστερόλη

Italiano (Italian)
colesterolo

Português (Portuguese)
n. - colesterol (m) (Quím.)

Русский (Russian)
холестерин

Español (Spanish)
n. - colesterol

Svenska (Swedish)
n. - kolesterol

中文（简体）(Chinese (Simplified))
胆固醇

中文（繁體）(Chinese (Traditional))
n. - 膽固醇

한국어 (Korean)
n. - 콜레스테롤

日本語 (Japanese)
n. - コレステロール

العربيه (Arabic)
‏(الاسم) كولسترول, دهن الصفراء, شحم المرارة‏

עברית (Hebrew)
n. - ‮כוהל מוצק שריכוז גבוה שלו בדם עלול לגרום הסתיידות עורקים, כולסטרול‬

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