Vol.3, # 24
June 24, 2006

Q: What is cholesterol and its importance in life? - Layperson

Cholesterol
Cholesterol
Chemical name 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
Chemical formula C27H46O
Molecular mass 386.65 g/mol
CAS number [57-88-5]
Melting point 146-147 °C
SMILES C[C@H]3C4[C@](CC[C@@H]4
[C@H](C)CCCC(C)C)([H])[C@]2
([H])CC=C1C[C@@H](O)CC[C@]1
(C)[C@@]2([H])C3

A:  Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. Lesser amounts of cholesterol are also found in plant membranes. The name originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol (C27H45OH) in solid form in gallstones in 1784.

Most cholesterol is not dietary in origin; it is synthesized internally. Cholesterol is present in higher concentrations in tissues which either produce more or have more densely-packed membranes, for example, the liver, spinal cord and brain, and also in atheroma. Cholesterol plays a central role in many biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport patterns and high levels of cholesterol in the blood.

Often, when most doctors talk to their patients about the health concerns of cholesterol, they are referring to "bad cholesterol", or low-density lipoprotein (LDL). "Good cholesterol" is high-density lipoprotein (HDL). Rarely mentioned is very low density lipoprotein (VLDL).

Very Low Density Lipoprotein (VLDL) is a lipoprotein subclass. It is assembled in the liver from cholesterol and apolipoproteins. It is converted in the bloodstream to low density lipoprotein (LDL). VLDL particles have a diameter of 30-80 nm. VLDL transports endogenous products where chylomicrons transport exogenous (dietary) products.

Function

VLDL transports endogenous triglycerides, phospholipids, cholesterol and cholesteryl esters. It functions as the body's internal transport mechanism for lipids.

Composition

Nascent (young) VLDL is released into the blood from the liver with the apolipoprotein B-100 (ApoB-100) marker. At this point, the VLDL consists of ~50% triglycerides, ~18% phospholipids, ~20% cholesterol and 10% protein (hence the name, very low density lipoprotein).

Changes During Circulation

Nascent VLDL circulates in blood and picks up apoliprotein C-II and apolipoprotein E donated from High Density Lipoprotein (HDL). At this point, the nascent VLDL becomes a mature VLDL. Once in circulation, the VLDL will come in contact with Lipoprotein Lipase (LPL) in the capillary beds in the body (adipose, cardiac and skeletal muscle). The LPL will remove triglycerides from the VLDL for storages or energy production.

The VLDL now meets back up with HDL where apoC-II is transferred back to the HDL (but keeps apoE). In addition to this, the HDL transfers cholesteryl esters to the VLDL in exchange for phospholipids and triglycerides (via cholesteryl ester transfer protein).

As more and more triglycerides are removed from the VLDL because of the action of the LPL enzyme, the composition of the molecule changes, and it becomes intermediate density lipoprotein (IDL).

50% of IDL are recognized by receptors in the liver cells (because of the apoB-100 and apoE they contain) and are endocytosed.

The other 50% of IDL loose their apoE. When their cholesterol content becomes greater than the triglyceride content, they become low-density lipoprotein (LDL), with the primary apolipoprotein being apoB-100. The LDL is taken into a cell via the LDL receptor (endocytosis) where the contents are either stored, used for cell membrane structure, or converted into other products (steroid hormones or bile acids).

VLDL and Disease

VLDL is prone to accelerate atherosclerosis, and is elevated in a number of diseases and metabolic states.

Physiology

Function

Cholesterol is required to build and maintain cell membranes; it makes the membrane's fluidity - degree of viscosity - stable over wider temperature intervals (the hydroxyl group on cholesterol interacts with the phosphate head of the membrane, and the bulky steroid and the hydrocarbon chain is embedded in the membrane). Some research indicates that cholesterol may act as an antioxidant. Cholesterol also aids in the manufacture of bile (which helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D, of the various steroid hormones, including cortisol and aldosterone in the adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone. Further recent research shows that cholesterol has an important role for the brain synapses as well as in the immune system, including protecting against cancer.

Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane. It also reduces the permeability of the plasma membrane to proton and sodium ions.

Properties

Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that are water-soluble and carry cholesterol and fats internally. The proteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied.

The largest lipoproteins, which primarily transport fats from the intestinal mucosa to the liver, are called chylomicrons. They carry mostly triglyceride fats and cholesterol (that are from food and especially internal cholesterol secreted by the liver into the bile). In the liver, chylomicron particles give up triglycerides and some cholesterol, and are converted into low-density lipoprotein (LDL) particles, which carry triglycerides and cholesterol on to other body cells. In healthy individuals the LDL particles are large and relatively few in number. In contrast, large numbers of small LDL particles are strongly associated with promoting atheromatous disease within the arteries. (Lack of information on LDL particle number and size is one of the major problems of conventional lipid tests.)

High-density lipoprotein (HDL) particles transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large numbers of large HDL particles correlates with better health outcomes. In contrast, having small amounts of large HDL particles is strongly associated with atheromatous disease progression within the arteries. (Note that the concentration of total HDL does not indicate the actual number of functional large HDL particles, another of the major problems of conventional lipid tests.)

The cholesterol molecules present in LDL cholesterol and HDL cholesterol are identical. The difference between the two types of cholesterol derives from the carrier protein molecules; the lipoprotein component.

Synthesis and intake

The HMG-CoA reductase pathway
The HMG-CoA reductase pathway

Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and tissues. About 20–25% of total daily production (~1 g/day) occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands and reproductive organs. For a person of about 150 pounds (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g and typical daily dietary intake is 200 to 300 mg. Of the 1,200 to 1,300 mg input to the intestines (via bile production and food intake), about 50% is reabsorbed into the bloodstream.Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism.

Regulation

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, while 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). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP (SREBP-cleavage activating protein) and Insig-1. 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 1/2 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) of a number of genes to stimulate their transcription. Among the genes transcribed 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. An excess of cholesterol in the bloodstream may lead to its accumulation in the walls of arteries. This build up is what can lead to clogged arteries and eventually to heart attacks and strokes.

A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein in the 1970s. They received the Nobel Prize in Physiology or Medicine for their work in 1985.

The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. There appear to be seasonal variations in cholesterol levels in humans, more, on average, in winter.

Excretion

Cholesterol is excreted from the liver in bile and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecithin and bilirubin gallstones also occur less frequently.

Clinical significance

Hypercholesterolemia 

In conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, cholesterol promotes 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 the only identified mechanism by which cholesterol can be removed from atheroma. Increased concentrations of HDL correlate with lower rates of atheroma progressions and even regression.

Of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis). Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. Conversely, 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.

These effects are further complicated by the relative concentration of asymmetric dimethylarginine (ADMA) in the endothelium, since ADMA down-regulates production of nitric oxide, a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for cardiovascular disease.

Multiple human trials utilizing HMG-CoA reductase inhibitors or statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lower cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults; however, no statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in asymptomatic people, i.e., no heart disease, no history of heart attack, etc.

Some of the better-designed recent randomized human outcome trials studying patients with coronary artery disease or its risk equivalents include the Heart Protection Study (HPS), the PROVE-IT trial, and the TNT trial. In addition, there are trials that have looked at the effect of lowering LDL as well as raising HDL and atheroma burden using intravascular ultrasound. Small trials have shown prevention of progression of coronary artery disease and possibly a slight reduction in atheroma burden with successful treatment of an abnormal lipid profile.

The American Heart Association provides a set of guidelines for total (fasting) blood cholesterol levels and risk for heart disease:

Level mg/dL Level mmol/L Interpretation
<200 <5.2 Desirable level corresponding to lower risk for heart disease
200-239 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), 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.

Patients should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle size. For cost reasons, LDL values have long been estimated using the Friedewald formula: [total cholesterol] - [total HDL] - 20% of the triglyceride value = estimated LDL. The basis of this is that Total cholesterol is defined as the sum of HDL, LDL, and VLDL. Ordinarily just the Total, HDL, and Triglycerides are actually measured. The VLDL is estimated as one-fifth of the Triglycerides. It is important to fast for at least 8-12 hours before the blood test because the triglyceride level varies significantly with food intake.

Increasing clinical evidence has strongly supported the greater predictive value of more-sophisticated testing that directly measures both LDL and HDL particle concentrations and size, as opposed to the more usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration.

Hypocholesterolemia

Abnormally low levels of cholesterol are termed hypocholesterolemia. Research into the causes of this state is relatively limited, and while some studies suggest a link with depression, cancer and cerebral hemorrhage it is unclear whether the low cholesterol levels are a cause for these conditions or an epiphenomenon].

Cholesterol in plants

Many sources (including textbooks) incorrectly assert that there is no cholesterol in plants. This misperception is made worse in the United States, where FDA rules allow for cholesterol quantities less than 2 mg/serving to be ignored in labelling. While plants sources contain much less cholesterol (Behrman and Gopalan suggest 50mg/kg of total lipids, as opposed to 5g/kg in animals), they still contain the substance, and require it to construct membranes.

Cholesteric liquid crystals

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


What Are Healthy Levels of Cholesterol?

Your total blood cholesterol level
Your total blood cholesterol will fall into one of these categories:

Desirable — Less than 200 mg/dL
Borderline high risk — 200–239 mg/dL
High risk — 240 mg/dL and over

Here is some more explanation about each of these categories.

Desirable
If your total cholesterol is less than 200 mg/dL, your heart attack risk is relatively low, unless you have other risk factors. Even with a low risk, it's still smart to eat foods low in saturated fat, trans fat and cholesterol, and also get plenty of physical activity. Have your cholesterol levels measured every five years — or more often if you're a man over 45 or a woman over 55.

Borderline high risk
People whose cholesterol level is from 200 to 239 mg/dL are borderline high risk. About a third of American adults are in this (borderline) group; almost half of adults have total cholesterol levels below 200 mg/dL.

Have your cholesterol and HDL rechecked in one to two years if:

  • Your total cholesterol is in this range.
  • Your HDL is less than 40 mg/dL.
  • You don’t have other risk factors for heart disease.
You should also lower your intake of foods high in saturated fat and cholesterol to reduce your blood cholesterol level to below 200 mg/dL. Your doctor may order another blood test to measure your LDL cholesterol. Ask your doctor to discuss your LDL cholesterol with you. Even if your total cholesterol is between 200 and 239 mg/dL, you may not be at high risk for a heart attack. Some people — such as women before menopause and young, active men who have no other risk factors — may have high HDL cholesterol and desirable LDL levels. Ask your doctor to interpret your results. Everyone's case is different.

High risk
If your total cholesterol level is 240 or more, it's definitely high. Your risk of heart attack and stroke is greater. In general, people who have a total cholesterol level of 240 mg/dL have twice the risk of coronary heart disease as people whose cholesterol level is 200 mg/dL.

You need more tests. Ask your doctor for advice. About 20 percent of the U.S. population has high blood cholesterol levels.

Your LDL cholesterol level
Your LDL cholesterol level greatly affects your risk of heart attack and stroke. The lower your LDL cholesterol, the lower your risk. In fact, it’s a better gauge of risk than total blood cholesterol. Your LDL cholesterol will fall into one of these categories:

LDL Cholesterol Levels
Less than 100 mg/dL Optimal
100 to 129 mg/dL Near Optimal/ Above Optimal
130 to 159 mg/dL Borderline High
160 to 189 mg/dL High
190 mg/dL and above Very High

The key point to remember is, the lower your LDL cholesterol, the lower your risk. Your doctor may prescribe a diet low in saturated fat and cholesterol, regular exercise and a weight management program if you're overweight. If you can't lower your cholesterol with these efforts, medications may also be prescribed to lower your LDL cholesterol. Check these categories and the goals for treatment that can lower your risk of heart attack.

LDL level at which to consider drug therapy

 
LDL Level
Goal
People without coronary heart disease and with fewer than two risk factors
190 mg/dL or higher*
160 mg/dL or lower
People without coronary heart disease and with two or more risk factors
160 mg/dL or higher
130 mg/dL or lower
People with coronary heart disease
130 mg/dL or higher**
100 mg/dL or lower

*In men less than age 35 and premenopausal women with LDL cholesterol levels of 190 to 219 mg/dL, drug therapy should be delayed except in high-risk patients such as those with diabetes.

**In coronary heart disease patients with LDL cholesterol levels of 100 to 129 mg/dL, the doctor should consider whether to initiate drug treatment in addition to the American Heart Association Therapeutic Lifestyle Changes (TLC) diet.

If you don't know if you have other risk factors for heart disease, check out the American Heart Association's list.

Your HDL cholesterol level
In the average man, HDL cholesterol levels range from 40 to 50 mg/dL. In the average woman, they range from 50 to 60 mg/dL. HDL cholesterol that's less than 40 mg/dL is low. Low HDL cholesterol puts you at high risk for heart disease. Smoking, being overweight and being sedentary can all result in lower HDL cholesterol. If you have low HDL cholesterol, you can help raise it by:

  • Not smoking
  • Losing weight (or maintaining a healthy weight)
  • Being physically active for at least 30–60 minutes a day on most or all days of the week

People with high blood triglycerides usually have lower HDL cholesterol and a higher risk of heart attack and stroke. Progesterone, anabolic steroids and male sex hormones (testosterone) also lower HDL cholesterol levels. Female sex hormones raise HDL cholesterol levels.

Cholesterol ratio
Total blood cholesterol is the most common measurement of blood cholesterol. It's the number you normally receive as test results. Cholesterol is measured in milligrams per deciliter of blood (mg/dL). Knowing your total blood cholesterol level is an important first step in determining your risk for heart disease. However, a critical second step is knowing your HDL or "good" cholesterol level.

Some physicians and cholesterol technicians use the ratio of total cholesterol to HDL cholesterol in place of the total blood cholesterol. The American Heart Association recommends that the absolute numbers for total blood cholesterol and HDL cholesterol levels be used. They're more useful to the physician than the cholesterol ratio in determining the appropriate treatment for patients.

The ratio is obtained by dividing the HDL cholesterol level into the total cholesterol. For example, if a person has a total cholesterol of 200 mg/dL and an HDL cholesterol level of 50 mg/dL, the ratio would be stated as 4:1. The goal is to keep the ratio below 5:1; the optimum ratio is 3.5:1.

Your triglyceride level
Your triglyceride level will fall into one of these categories:

Triglyceride Level Classification
Less than 150 mg/dL Normal
150–199 mg/dL Borderline-high
200–499 mg/dL High
500 mg/dL or higher Very high

Many people with high triglycerides have underlying diseases or genetic disorders. If this is true for you, the main therapy is to change your lifestyle. This includes controlling your weight, eating foods low in saturated fat, trans fat and cholesterol, exercising regularly, not smoking and, in some cases, drinking less alcohol. People with high triglycerides may also need to limit their intake of carbohydrates to no more than 45–50 percent of total calories. The reason for this is that carbohydrates raise triglycerides in some people and lower HDL cholesterol. Use products with monounsaturated and polyunsaturated fats.

Overall  total cholesterol levels should be below 200 mg/dl. (130-140 mg./dl. associated with little or no plaque build up in the arteries) and HDL at least 25% of the total, even if the overall total cholesterol is higher than 200 mg./dl.. An interesting point to make is at any given time, 50-75% of the heart attack victims have had normal or near normal total cholesterol levels.



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DISCLAIMER:  The information in this column, is NOT intended to diagnose and/or treat any health related issues and is provided solely for informational purposes only. Consult the appropriate healthcare professional before making any changes to your healthcare regime. Even what may seem like simple changes in the diet for example, can interact with, and alter, the efficiency of medications and/or the body's response to the medications. Many herbs and supplements exert powerful medicinal effects. Neither the author, nor the website designers, assume any responsibility for the reader's use or misuse of this information.

© 2002 Nature's Corner