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Cholesterol
Cholesterol is a lipid of the family sterols, which plays a central role in many biochemical processes. The cholesterol gets its name from ancient Greek chole-(bile) and stereos (solid), because it was discovered in solid form in gallstones in 1769 by François Poulletier de la Salle. But it was not until 1815 that the chemist french Eugene Chevreul gave him the name of cholestérine.
The study of this molecule has often been rewarded by Nobel Prize:
* In 1964, Konrad Bloch and Feodor Lynen received the Nobel Prize for Medicine for "their discovery on the mechanism for regulating cholesterol metabolism and fatty acids";
* In 1965, Robert Burns Woodward received the Nobel Prize in Chemistry for his "outstanding achievements in the art of organic synthesis". It was the first to realize the chemical synthesis of cholesterol and cortisone in 1951;
* In 1985, Michael S. Brown and Joseph L. Goldstein received the Nobel Prize for Medicine for "their discovery on the regulation of cholesterol metabolism".
The word "cholesterol" means a molecule and should not be confused with the words "good" and "bad cholesterol" referring to HDL and LDL, carriers of cholesterol in the blood.
Structure
The cholesterol molecule consists of four carbon cycles noted A, B, C and D (kernel cyclo-pentano-phenanthrene), 8 asymmetric carbon (carbon 3, 8, 9, 10, 13, 14, 17 and 20), which is 28 or 256 stereoisomers including one exists: the β 3-ol lévogyre. Cholesterol has a hydroxyl group-OH on carbon 3 (C3). This chemical group is very hydrophobic with a coefficient of solubility of 5 micromoles. The function OH cholesterol may be esterified by a fatty acid molecule that makes totally insoluble in water.
Almost all cycles steroids take the form called "chair", conformation most stable thermodynamically. The hinges between cycles B and C, and C and D are still in trans configuration.
Location
Cholesterol is present in the form of sterides (cholesterol ester) in most tissues of vertebrates, and especially the liver, brain and spinal cord.
Role
It is a major component of cell membranes, which contributes to its stability and maintain their structures s'intercalant between phospholipids.
Cholesterol is also a precursor of many molecules:
* Vitamin D3, which is involved in the calcification of bones,
* Steroid hormones: cortisol, cortisone, and aldosterone,
* Sexual hormones steroids: progesterone, estrogen and testosterone,
* Bile acids,
Overview
The synthesis of cholesterol is in the cytoplasm of cells in the liver and intestine mainly. The synthesis begins with the condensation of three molecules acetate (= 3 x 2 carbons) hydroxy-methyl-glutarate (or HMG = 1 × 6 carbons). This synthesis is carried out by the hydroxyméthylglutaryl-Coenzyme A synthase (or HMGCoA synthase), an enzyme in the presence of coenzyme A, an enzyme cofactor. The hydroxy-methyl-glutarate is then reduced to mévalonate (= 1 × 6 carbons). This step is regulated by the statins. The mévalonate is then décarboxylé in isoprènoïdes a 5-carbon (isopentényl pyrophosphate and diméthylallyl pyrophosphate). The condensation of 6 molecules isoprènoïdes ultimately leads to squalene (6 x 5 = 30 carbons). Finally, squalene undergoes the action of squalene cyclase which created the cycles cholésterol from unsaturations in squalene.
Regulation
There are three levels of regulation of cholesterol, with the aim of reducing cholesterol levels of the cell when it is in excess:
* The free cholesterol in cell inhibits the production of its own membrane receptors LDLR. To do so, it inhibits the transcription of the gene that encodes the LDLR. Hence, the inflow of cholesterol in the cell is decreased.
* The free cholesterol inhibits HMG-coA reductase, which prevents further reaction synthesis of cholesterol.
* Finally, cholesterol free stimulates acyl transferase (ACAT), an enzyme catalyzing its esterification in stéride. This promotes the storage of cholesterol free.
The synthesis of mévalonate second stage of the synthesis of cholesterol, is highly regulated by the metabolism. The activity of HMG-CoA reductase enzyme catalyzing the synthesis, is reduced when dietary cholesterol is high or with drugs of the family of statins. Approximately one third of cholesterol comes from food (meat, eggs, offal, dairy products, etc..) While the remaining two thirds are synthesized by the body (in the case of a balanced diet).
Degradation
Cholesterol is degraded in the liver bile acids (chenodeoxycholic acid) by 7 - α-hydroxylase. The Cholestyramine, a drug used to treat high cholesterol, decreases intestinal absorption of bile acids, and hence their concentration in the liver cells. This leads to an activation of 7 - α-hydroxylase and promote the degradation of cholesterol.
Transport of cholesterol in the blood: LDL, VLDL and HDL
As a compound hydrophobic, cholesterol is not soluble in blood. His transportation is provided by four types of lipoproteins:
* The low-density lipoprotein (LDL: Low Density Lipoprotein) carry cholesterol places secretion to the body's cells. Important rates of LDL generally lead to the filing of cholesterol on artery walls (LDL receptors in the liver and tissues are very sensitive to any change of a biochemical LDL, as a result of oxidation or degradation due to cigarette smoke or other factors, carrying lipoprotein cholesterol are no longer recognized, and are therefore phagocytées, then make a deposit) in the form of plate atheroma, which increases the risk of cardiovascular disease and is the name of "bad" cholesterol;
* The high-density lipoprotein (HDL: High Density Lipoprotein) unloading the arteries and tissues extrahepatic cholesterol, and bring to the liver where it is degraded are called "good" cholesterol;
* Chylomicrons these lipoproteins carry lipids (cholesterol included) from the intestine into other tissues
* The lipoproteins at very low density (or VLDL: Very Low Density lipoprotein).
Cholesterol content in food
These levels of dietary cholesterol be completed and relativized by:
* Levels of saturated fatty acids (which may increase the rates in LDL) and trans unsaturated (may increase rates to lower LDL and HDL rates)
* Levels of fatty acids mono-unsaturated and poly-unsaturated.
* The dietary intake of antioxidants (eg vitamin E, vitamin C, β-carotene) may limit the accumulation of LDL in the arterial wall.
It must finally and most importantly clear that dietary intake of cholesterol plays only 10% (maximum) in the cholesterol of an individual. [Ref. necessary]
The cholesterol present in VLDL and LDL comes in effect tissue (where there is surplus) who synthesized, and not of chylomicrons (structure of lipid transport from the intestine). Limiting dietary intake of cholesterol, or its absorption in the intestine (through the absorption intensive phytosterols, for example) for an individual who does not have familial hypercholesterolemia has, therefore, that little 'effect-health prevention.
Hypercholesterolemia and atherosclerosis
From the early nineteenth century, the work of Anitschkow and Chalatow had revealed a role of cholesterol in experimental atherosclerosis in rabbits. Today, several studies have shown that atherosclerosis is an inflammatory disease and that the agent aggressor is very probably associated with LDL cholesterol after oxidation. Meanwhile, several studies have highlighted a link between cholesterol and the presence of an inflammatory reaction in the vascular tissue. Today, the important role of cholesterol and LDL in atherosclerosis seems well established, especially since clinical trials of primary and secondary prevention in patients hypercholestérolémiques have demonstrated that it was possible to reduce the incidence of heart disease ischemic lowering the LDL cholesterol associated with statins.
The role of cholesterol in atherosclerosis was also considered a dietary point of view. During the years 1950-1960, U.S. Ancel Keys develops lipid hypothesis that a link between blood cholesterol and the risk of cardiovascular disease. Regular physical activity, alcohol and low-dose estrogen may help to increase HDL, limiting blood cholesterol and improving the protection vascular [ref. necessary]. Conversely, tobacco, obesity and inactivity promote the reduction of HDL in the blood, increasing cardiovascular risk [ref. necessary]. Few people, however, bring into question the assumption of lipid Ancel Keys commonly accepted that excessive consumption of fats and cholesterol would be the principal cardiovascular diseases [16]. These opinions are qualified by the fact that the relationship between blood cholesterol and increased cardiovascular risk seems solidly established and longstanding clinical studies and epidemiological.
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