Cholesterol

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 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.

Contents
1 History of the name
2 Physiology
2.1 Function
2.2 Properties
2.3 Synthesis and intake
2.4 Regulation
2.5 Excretion
3 Role in atheromatous disease
4 Cholesteric liquid crystals 
 
History of the name
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.

Recommended reading: Effective Ways To Lower Your Cholesterol

Physiology

Function
Cholesterol is an important component of the membranes of cells, providing stability; it makes the membrane's fluidity - degree of viscosity - 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 also reduces the permeability of the plasma membrane to proton and sodium ions (Haines 2001). 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.

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.

Synthesis and intake
 
The HMG-CoA reductase pathwayCholesterol 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 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 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 can build up in the bloodstream and accumulates on the walls of arteries. This build up is what can lead to clogged ateries 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. A study by Ockene et al. showed that there are 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.

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.