CHOLESTEROL   from http://en.wikipedia.org/wiki/Cholesterol

Cholesterol, from the Ancient Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol, is an organic molecule. It is a sterol (ormodified steroid),^[3] and an essential structural component of animal cell membranes that is required to establish proper membrane permeability and fluidity. Cholesterol is thus considered within the class of lipid molecules. In addition to its importance within cells, cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acids, and vitamin D.^[4] Cholesterol is the principal sterol synthesized by animals; in vertebrates it is formed predominantly in the liver.

François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until 1815 that chemist Michel Eugène Chevreul named the compound "cholesterine".^[5][6]  Since cholesterol is essential for all animal life, each cell synthesizes it from simpler molecules, a complex 37-step process that starts with the intracellular protein enzyme HMG-CoA reductase [what statins block]. However, normal and particularly high levels of fats (including cholesterol) in the blood circulation, depending on how they are transported within lipoproteins, are strongly associated with the progression of atherosclerosis.  For a man of about 68 kg (150 pounds), typical total body-cholesterol synthesis is approximately 1 g (1,000 mg) per day, and total body content is approximately 35 g, primarily located within the membranes of all the cells of the body. Typical daily dietary intake of additional cholesterol, in the United States, is 200–300 mg.^[7]  Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. The body also compensates for any absorption of additional cholesterol by reducing cholesterol synthesis.^[8] For these reasons, cholesterol intake in food has little, if any, effect on total body cholesterol content or concentrations of cholesterol in the blood.  Cholesterol is recycled. The liver excretes it in a non-esterified form (via bile) into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream.

Function[edit]

Cholesterol is required to build and maintain membranes; it modulates 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. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.^[11] The structure of the tetracyclic ring of cholesterol contributes to the decreased fluidity of the cell membrane as the molecule is in a trans conformation making all but the side chain of cholesterol rigid and planar.^[12] In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes,^[13] protons, (positive hydrogen ions) and sodium ions.^[14]

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. Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messenger molecules.^[15] Cholesterol levels can change how quickly surface proteins move within the plasma membrane^[16] and also the efficiency of magnetic capture of cells.^[17] 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.^[18]

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, A, D, E, and K. Cholesterol is an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol andaldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.^[4] Some research indicates cholesterol may act as an antioxidant.^[19]

Dietary sources

Fat intake also plays a role in blood-cholesterol levels. This effect is thought^{[by whom?]} to come about by changes in the quantity of cholesterol and lipoproteins that are synthesized by the body. Isocalorically replacing dietary carbohydrates withmonounsaturated and polyunsaturated fats has been shown to lower serum LDL and total cholesterol levels and increase serum HDL levels, while replacing carbohydrates with saturated fat was shown to increase HDL, LDL, and total cholesterol levels.^[29] Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.^[30] Based on such evidence and evidence implicating low HDL and high LDL levels in cardiovascular disease (see Hypercholesterolemia), many health authorities advocate reducing LDL cholesterol through changes in diet in addition to other lifestyle modifications.^[31] The USDA, for example, recommends that those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily energy needs from saturated fat and fewer than 200 mg of cholesterol per day.^[32] An alternative view is that any reduction to dietary cholesterol intake could be counteracted by the organs compensating to try to keep blood cholesterol levels constant.^[33] Other research has found that an increase in the consumption of saturated fats and cholesterol decreases overall serum cholesterol. ^[34].

Regulation of cholesterol synthesis[edit]

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).^[37]

Plasma transport and regulation of absorption

Cholesterol  is transported in the circulatory system within lipoproteins, complex discoidal particles that 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 in 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 lipid and less protein a lipoprotein has, the less dense it is.  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. 

LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester. LDL molecules, therefore, are the major carriers of cholesterol in the blood, and each one contains approximately 1,500 molecules of cholesterol ester.  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.  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 atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness).^[40] 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.^[39]

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).^[41] Having large numbers of large HDL particles correlates with better health outcomes.^[42] In contrast, having small numbers of large HDL particles is independently associated with  atheromatous disease progression in the arteries.  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.

Metabolism, recycling and excretion

Cholesterol is oxidized by the liver into a variety of bile acids.^[46] These, in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. A mixture of conjugated and nonconjugated bile acids, along with cholesterol itself, is excreted from the liverinto the bile. Approximately 95% of the bile acids are reabsorbed from the intestines, and the remainder are lost in the feces.^[47] 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.