Cholesterol

The cholesterol is a Lipide of the family of the Stérol S which plays a central role in many biochemical processes . Cholesterol draws its name from the old Greek chole- (Bile) and from stereophonies (solid), because he was discovered in solid form in the gallstones in 1769 by François Poulletier of the Room. But it is only into 1815 that the French chemist Eugene Chevreul gave him the name of cholestérine .

The study of this molecule was often rewarded by Nobel Prize:

  • in 1964, Konrad Bloch and Feodor Lynen accepted the Nobel Prize of medicine for “their discovery concerning the mechanism of regulation of the metabolisms of cholesterol and the fatty-acids”;
  • in 1965, Robert Burns Woodward accepted the Nobel Prize of chemistry for “its exceptional achievements in the art of the organic synthesis”. It was the first to carry out the chemical synthesis of cholesterol and the Cortisone in 1951;
  • in 1985, Michael S. Brown and Joseph L. Goldstein accepted the Nobel Prize of medicine for “their discovery relating to the regulation of the metabolism of cholesterol”.

The word “cholesterol” indicates a molecule and does not have to be confused with the terms of “good” and “bad cholesterol” referring to the HDL and LDL, the conveyers of cholesterol in blood.

Structure

The Molécule of cholesterol includes/understands four carbonaceous cycles noted has, B, C and D (cyclo-pentano-phénanthrénique core), 8 asymmetrical carbons (carbons 3,8,9,10,13,14,17 and 20), which makes 2 is 256 stéréoisomère S of which only one exists: the Laevogyrous 3β-ol . Cholesterol has a group Hydroxyle on carbon 3 (C3). This chemical group is very Hydrophobe with a coefficient of Solubilité of 5 micromoles. Function OH of cholesterol can be esterified by a Fatty-acid which makes the molecule completely insoluble in water.

Almost all the cycles steroids take the form known as “chair”, the conformation most stable thermodynamically. Hinges between the cycles B and C, and C and D are always in configuration trans . trans or cis of methyl in C19, fixed: By considering that methyl in C19 is above the plan, 5α wants to say that the substituent in C5 is below the plan, and 5β above the plan. -->

Localization

Cholesterol is present in the form of Stéride S (esterified cholesterol) in the majority of fabrics of the Vertébré S, and in particular the Foie, the Cerveau, and the Spinal-cord.

Role

In fact component major cellular membranes contributes to their stability and the maintenance of their structures while being intercalated between the Phospholipide S.

Cholesterol is also a precursor of many molecules:

Metabolism

Synthesis

The synthesis of cholesterol is made in the Cytoplasme cells of the Foie and intestine mainly. The synthesis begin with condensation from three molecules from Acétate (=3×2 carbons) in hydroxy-methyl-glutarate (or HMG = 1×6 carbons). This synthesis is made by the hydroxyméthylglutaryl-Coenzyme has synthase (or HMGCoA synthase), a Enzyme, in the presence of Coenzyme has, a Cofacteur of enzyme. The hydroxy-methyl-glutarate is then tiny room in mévalonate (=1×6 carbons). This stage is controlled by the statines. The mévalonate is then décarboxylé in isoprènoïde S with 5 carbons ( the isopentényl pyrophosphate and the diméthylallyl pyrophosphate ). The condensation of 6 molecules of isoprènoïdes leads finally to the Squalène (6×5=30 carbons). Lastly, the Squalène undergoes the action of the squalene cyclase which created the cycles of cholesterol starting from the non-saturation S present in squalene.

Regulation

There exist three levels of regulation of cholesterol, the goal being to decrease the cholesterol level of the cell when it is in excess:
  • free cholesterol in the cell inhibits the production of its own membrane receivers LDLR. With this intention, it inhibits the transcription of the gene which codes the LDLR. Consequently, the cholesterol flow entering the cell is decreased.
  • free cholesterol inhibits HMG-coA réducatase, which prevents the continuation of the reaction of synthesis of cholesterol.
  • Lastly, free cholesterol stimulates the acyl transférase (ACAT), enzyme catalyzing its esterification in Stéride. This supports the storage of free cholesterol.

The synthesis of mévalonate, second phase of the synthesis of cholesterol, is very controlled by the metabolism. The activity of HMG-CoA réductase, Enzyme catalyzing this synthesis, is decreased when the cholesterol food supply is raised or by drugs of the family of the Statine S. Environ a third of cholesterol comes from food (meats, eggs, meat offals, dairy products, etc) while remaining two thirds are synthesized by the organization (in the case of a balanced food).

Degradation

Cholesterol is degraded in the Foie in biliary acids (of which acid chenodesoxycholic) by the 7-α-hydroxylase. The colestyramine, a drug used to treat the Hypercholestérolémie, decreases the intestinal absorption of the biliary acids, and consequently their concentration in the hepatic cells. This involves an activation of the 7-α-hydroxylase and supporting the degradation of cholesterol.

Transport of cholesterol in blood: LDL, VLDL and HDL

Being a Hydrophobic compound , cholesterol is not soluble in blood. Its transport is ensured by four types of Lipoprotéine S:

  • the lipoproteins with low density (or LDL: Low Density Lipoprotein ) transports the cholesterol of the places of secretion towards the cells of the organization. Important rates of LDL generally lead to the cholesterol deposit on the walls of the arteries (the receivers with LDL of the liver and of fabrics are indeed very sensitive: with the least biochemical change of a LDL, because of an oxidation or degradation dependant on the cigarette smoke or other factors, the lipoproteins transporting cholesterol are not recognized any more, and are thus phagocytées, then form a deposit) in the form of plate of Athérome, which increases the disease risk cardiovascular and the name of “bad” cholesterol is worth to them;

  • the lipoproteins with high density (or HDL: High Density Lipoprotein ) discharges the arteries and fabrics extrahepatic from cholesterol, and bring back it towards the liver where it is degraded; one speaks then about “good” cholesterol;

  • the Chylomicron S; these lipoproteins ensure the transport of the lipids (cholesterol included) of the intestine towards the other fabrics

  • the lipoproteins with very low density (or VLDL: Very Low Densty lipoprotein ).

Content cholesterol in the food

These contents food cholesterol are to be supplemented and relativize by:

  • contents of saturated fatty-acids (being able to increase the rates in LDL) and unsaturated trans (being able to increase the rates in LDL and to lower the rates in HDL)
  • contents of fatty-acids mono-unsaturates and poly-unsaturates.
  • the food supply of antioxydants (p.ex. Vitamin E, Vitamin C, β-carotene) which can limit the accumulation of the LDL in the arterial wall.

It is necessary finally and especially to specify that the food absorption of cholesterol plays only 10% (to the maximum) in the cholesterolemy of an individual. Cholesterol present in the VLDL and LDL comes indeed from the fabrics (where it is surplus) which synthesized it, and by no means will chylomicrons (structure of transport of the lipids coming from the intestine). To limit the cholesterol food supplies, or its absorption on the level of the intestine (through the intensive absorption of Phytosterols, for example), for an individual not suffering from family hypercholesterolemy, has consequently only little prevention-health effect.

Pathologies

Hypercholesterolemy and athérosclérose

See also: Hypercholestérolémie

The beginning of, work of Anitschkow and Chalatow had made it possible to highlight a role of cholesterol in the experimental Athérosclérose in rabbit. Today, several studies showed that the athérosclérose is a inflammatory disease and that the agent attacker is most probably cholesterol associated with LDL after oxidation. In parallel, several studies highlighted a bond between Hypercholestérolémie and presence of a inflammatory reaction in the vascular Tissu. Today, the important role of cholesterol and the LDL in the athérosclérose seems well established, in particular since the clinical trials of primary and secondary prevention at the hypercholesterolemic subjects showed that it was possible to reduce the frequency of the ischemic cardiopathies by decreasing cholesterol associated with the LDL using Statine S.

The role of cholesterol in the athérosclérose was also studied of a point of the dietetic sight. During years 1950-1960, American Ancel Keys develops the lipidic assumption establishing a link between the rate of blood cholesterol and Cardiovascular disease risks it. The regular physical-activity, alcohol with low dose and the estrogens could contribute to increase the rate of HDL, limiting the blood cholesterol level and improving vascular protection. Conversely, the tobacco, obesity and the inactivity support the reduction in the rate of HDL in blood, increasing the cardiovascular risk. Rare are those which however question the assumption lipidic of Ancel Keys, commonly allowed, according to which the excess of consumption of greases and cholesterol would be the principal person in charge of the cardiovascular diseases. These opinions are to be moderated by the fact that the relation between the blood cholesterol level and the increase in the cardiovascular risk seems established firmly and of long time by the clinical studies and epidemiologic

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