cholesterol

Physiology
Since cholesterol is essential for all animal life, each cell synthesizes it from simpler molecules, a complex 37-step process which starts with the intracellular protein enzyme HMG-CoA reductase . However, normal and especially high levels of fats (including cholesterol) within the blood circulation, depending on how it is transported within lipoproteins , are strongly associated with progression of atherosclerosis .
For a man 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, primarily located within all the membranes of all the cells of the body. Typical daily dietary intake of additional cholesterol, in the United States, is 200–300 mg.
However, 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. 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.
Some plants make cholesterol in very small amounts. Plants manufacture phytosterols (substances chemically similar to cholesterol produced within plants), which can compete with cholesterol for reabsorption in the intestinal tract, thus potentially reducing cholesterol reabsorption. However, phytosterols are foreign to animal cells and, if absorbed, accelerate the progression of atherosclerosis . [ citation needed ] When intestinal lining cells absorb phytosterols, in place of cholesterol, they usually excrete the phytosterol molecules back into the GI tract, an important protective mechanism.
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 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 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 lipid 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 that is not used by muscles remains in more cholesterol-rich chylomicron remnants, which are taken up from here to 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 shells. During transport in the bloodstream, the blood vessels cleave and absorb more triacylglycerol from IDL molecules, which contain an even higher percentage of cholesterol. The IDL molecules have two possible fates: Half are into metabolism by HTGL , taken up by the LDL receptor on the liver cell surfaces, 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 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 atherosclerotic plaque formation. Differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness). 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.
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). Having large numbers of large HDL particles correlates with better health outcomes. 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 susceptible to oxidation and easily forms oxygenated derivatives known as oxysterols . Three different mechanisms can form these; autoxidation, secondary oxidation to lipid peroxidation, and cholesterol-metabolizing enzyme oxidation. A great interest in oxysterols arose when they were shown to exert inhibitory actions on cholesterol biosynthesis. This finding became known as the “oxysterol hypothesis”. Additional roles for oxysterols in human physiology include their: participation in bile acid biosynthesis, function as transport forms of cholesterol, and regulation of gene transcription.
In biochemical experiments radiolabelled forms of cholesterol, such as tritiated-cholesterol are used. These derivatives undergo degradation upon storage and it is essential to purify cholesterol prior to use. Cholesterol can be purified using small Sephadex LH-20 columns.
Cholesterol is oxidized by the liver into a variety of bile acids . 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 liver into the bile . Approximately 95% of the bile acids are reabsorbed from the intestines, and the remainder are lost in the feces. 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, but less frequently. Every day, up to 1 g of cholesterol enters the colon. This cholesterol originates from the diet, bile, and desquamated intestinal cells, and can be metabolized by the colonic bacteria. Cholesterol is converted mainly into coprostanol , a nonabsorbable sterol that is excreted in the feces. A cholesterol-reducing bacterium origin has been isolated from human feces.