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Cholesterol | Understanding and definition of cholesterol | The cause of cholesterol

Understanding and definition of cholesterol
Cholesterol is a waxy steroid of fat that is manufactured in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes. It is required to establish proper membrane permeability and fluidity. In addition cholesterol is an important component for the manufacture of bile acids, steroid hormones, and Vitamin D. Cholesterol is the principal sterol synthesized by animals; however, small quantities can be synthesized in eukaryotes such as plants and fungi. It is almost completely absent among prokaryotes including bacteria. Although cholesterol is important and necessary for mammals, high levels of cholesterol in the blood can damage arteries and are potentially linked to diseases such as those associated with the cardiovascular system (heart disease).
The name cholesterol originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol. François Poulletier de la Salle first identified cholesterol in solid form in gallstones, in 1769. However, it was only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".

Since cholesterol is essential for all animal life, it is primarily synthesized from simpler substances within the body. However, high levels in blood circulation, depending on how it is transported within lipoproteins, are strongly associated with progression of atherosclerosis. For a person 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. Typical daily additional dietary intake in the United States is 200–300 mg. The body compensates for cholesterol intake by reducing the amount synthesized.

Cholesterol is recycled. It is excreted by the liver via the bile into the digestive tract. Typically about 50% of the excreted cholesterol is reabsorbed by the small bowel back into the bloodstream. Phytosterols can compete with cholesterol reabsorption in the intestinal tract, thus reducing cholesterol reabsorption.

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. In this structural role, cholesterol reduces the permeability of the plasma membrane to protons (positive hydrogen ions) and sodium ions.

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. 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.

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, Vitamin A, Vitamin D, Vitamin E, and Vitamin K. Cholesterol is an important precursor molecule for the synthesis of Vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.

Animal fats are complex mixtures of triglycerides, with lesser amounts of phospholipids and cholesterol. As a consequence, all foods containing animal fat contain cholesterol to varying extents. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp.

Human breast milk also contains significant quantities of cholesterol.

The amount of cholesterol present in plant-based food sources is generally much lower than animal based sources. In addition, plant products such as flax seeds and peanuts contain cholesterol-like compounds called phytosterols, which are suggested to help lower serum cholesterol levels.

Total fat intake, especially saturated fat and trans fat, plays a larger role in blood cholesterol than intake of cholesterol itself. Saturated fat is present in full fat dairy products, animal fats, several types of oil and chocolate. Trans fats are typically derived from the partial hydrogenation of unsaturated fats, and do not occur in significant amounts in nature. Trans fat is most often encountered in margarine and hydrogenated vegetable fat, and consequently in many fast foods, snack foods, and fried or baked goods.

A change in diet in addition to other lifestyle modifications may help reduce blood cholesterol. Avoiding animal products may decrease the cholesterol levels in the body not only by reducing the quantity of cholesterol consumed but also by reducing the quantity of cholesterol synthesized. Those wishing to reduce their cholesterol through a change in diet should aim to consume less than 7% of their daily energy needs {metric units Joules (J) or (kJ), pre-SI calories (Cal) or (kcal)} from animal fat and fewer than 200 mg of cholesterol per day.

It is debatable that a diet, changed to reduce dietary fat and cholesterol, can lower blood cholesterol levels, (and thus reduce the likelihood of development of, among others, coronary artery disease leading to coronary heart disease), because any reduction to dietary cholesterol intake could be counteracted by the organs compensating to try to keep blood cholesterol levels constant. Also pointed out is the experimental discovery that in the diet, ingested animal protein can raise blood cholesterol more than the ingested saturated fat or any cholesterol. Moreover, the benefits of a diet supplemented with plant sterol esters has been questioned.

All animal cells manufacture cholesterol with relative production rates varying by cell type and organ function. About 20–25% of total daily cholesterol production occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands, and reproductive organs. Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step is the regulated, rate-limiting and irreversible step in cholesterol synthesis and is the site of action for the statin drugs (HMG-CoA reductase competitive inhibitors).

Mevalonate is then converted to 3-isopentenyl pyrophosphate in three reactions that require ATP. This molecule is decarboxylated to isopentenyl pyrophosphate, which is a key metabolite for various biological reactions. Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally, lanosterol is then converted to cholesterol.

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 which 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 cholesterol 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 which is not used by muscles remains in more cholesterol-rich chylomicron remnants, which are taken up from 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 shell. During transport in the bloodstream, the blood vessel 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 that 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 artherosclerotic 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.

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 it was shown they 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.

According to the lipid hypothesis, abnormal cholesterol levels (hypercholesterolemia)—that is, higher concentrations of LDL and lower concentrations of functional HDL—are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke, and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles, LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to as "good cholesterol". These balances are mostly genetically determined but can be changed by body build, medications, food choices, and other factors.

Conditions with elevated concentrations of oxidized LDL particles, especially "small dense LDL" (sdLDL) particles, are associated with 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 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. A 2007 study pooling data on almost 900,000 subjects in 61 cohorts demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. Still, because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is still larger in older people.

Elevated levels 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. On the converse, 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. Recently, a post-hoc analysis of the IDEAL and the EPIC prospective studies found an association between high levels of HDL cholesterol (adjusted for apolipoprotein A-I and apolipoprotein B) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol".

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