Cholesterol

Cholesterol chemical structure

Cholesterol is a steroid, a lipid, and an alcohol, found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. 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, brain and 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 in the blood.

History of the name

The name originates from the Greek chole- (bile) and stereos (solid), as researchers first identified cholesterol (C₂₇H₄₅OH) in solid form in gallstones.

Physiology

Synthesis and intake

The HMG-CoA reductase pathway

Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells/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.

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 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.

Regulation

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake in food leads to a net decrease in endogenous production and vice versa. 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 "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.If an excess of cholesterol is build up in the bloodstream and accumulate on the walls of arteries which can clog the blood vessels and lead 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. A study by Ockene et al. showed that there are seasonal variations in cholesterol levels in humans, more, on average, in winter.

Function

Cholesterol is an important component of the membranes of cells, providing stability; it makes the membrane's fluidity stable over a bigger temperature interval. 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. It is the major precursor for the synthesis of vitamin D, of the various steroid hormones, including cortisol, cortisone, and aldosterone in the adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone. The presence of cholesterol has a direct effect on the fluidity of the membrane. 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.

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.

Role in atheromatous disease

See also the main article hypercholesterolemia

In conditions with elevated concentrations of LDL particles, especially small LDL particles, cholesterol promotes atheroma plaque deposits in the walls of arteries, a condition known as atherosclerosis, which is a major contributor to coronary heart disease and other forms of cardiovascular disease. (In contrast, HDL particles have been the only identified mechanism by which cholesterol can be removed from atheroma. Increased concentrations of large HDL particles, not total HDL particles, correlate with lower rates of atheroma progressions, even regression.)

There is a world-wide trend to believe that lower total cholesterol levels tend to correlate with lower atherosclerosis event rates. Due to this reason, cholesterol has become a very large focus for scientific researchers trying to determine the proper amount of cholesterol needed in a healthy diet.However, the primary association of atherosclerosis with cholesterol has always been specifically with cholesterol transport patterns, not total cholesterol per se. For example, total cholesterol can be low, yet made up primarily of small LDL and small HDL particles and atheroma growth rates are high. In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large (HDL is actively reverse transporting cholesterol), then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration.

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 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:

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 formula: Total-cholesterol − total-HDL − 20% of the triglyceride value = estimated LDL.

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. There are three commercial labs in the United States that offer more-sophisticated analysis using different methodologies. As outlined above, the real key is cholesterol transport, which is determined by both the proteins that form the lipoprotein particles and the proteins on cell surfaces with which they interact.

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.

See also

• triglycerides

Sources

• Anderson RG. Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol 2003:13:534-9. PMID 14507481.
• Ockene IS, Chiriboga DE, Stanek EJ 3rd, Harmatz MG, Nicolosi R, Saperia G, Well AD, Freedson P, Merriam PA, Reed G, Ma Y, Matthews CE, Hebert JR. Seasonal variation in serum cholesterol levels: treatment implications and possible mechanisms. Arch Intern Med 2004;164:863-70. PMID 15111372.

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
• A review of scientific studies on the cholesterol lowering potential of tocotrienols in comparison with statins
• The Weston A. Price Foundation is a group that questions the connection between cholesterol and atheroma.
• Cholesterol and Health (alternative views on cholesterol's relationship to disease)
• The Cholesterol Myths Uffe Ravnskov, M.D., Ph.D.