Sandbox 215: Difference between revisions

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Binding to a HDL particle, which is cholesteryl ester rich, allows CETP to fill with cholesteryl esters, because one or two cholesteryl esters can enter the tunnel and an equal amount of triglyceride is deposited into HDL. Then the tunnel is refilled with two phospholipid (one at each end) that permits the protein to dissociate from HDL and to retunr to the acqueous phase. CETP also adopts a structural change by twisting its barrel around the central β-sheet in order to bind VLDL particules which are larger than HDL particules. Binding to a VLDL particle, which is triglyceride rich, permits the release of the bound phospholipid. That allows one or two triglycerides to enter the tunnel and an equal amount of cholesteryl ester can be deposit into VLDL. The triglyceride-bound dissociates from VLDL. It carries two phospholipids from the surface of VLDL and travels through the acqueous plasma in order to rebind a HDL particle. Binding to a HDL particle, permits the release of the bound phospholipid and the cycle can continue.
Binding to a HDL particle, which is cholesteryl ester rich, allows CETP to fill with cholesteryl esters, because one or two cholesteryl esters can enter the tunnel and an equal amount of triglyceride is deposited into HDL. Then the tunnel is refilled with two phospholipid (one at each end) that permits the protein to dissociate from HDL and to retunr to the acqueous phase. CETP also adopts a structural change by twisting its barrel around the central β-sheet in order to bind VLDL particules which are larger than HDL particules. Binding to a VLDL particle, which is triglyceride rich, permits the release of the bound phospholipid. That allows one or two triglycerides to enter the tunnel and an equal amount of cholesteryl ester can be deposit into VLDL. The triglyceride-bound dissociates from VLDL. It carries two phospholipids from the surface of VLDL and travels through the acqueous plasma in order to rebind a HDL particle. Binding to a HDL particle, permits the release of the bound phospholipid and the cycle can continue.


==CETP inhibitors==
==CETP inhibition==


Cholesterol is the major lipid component of the plasma membrane of the animal cells. Cholesterol is also a constituent of lipoprotein complexes in the blood and one of the constituents of lipoprotein complexes of the plaques that form on the blood vessels by atherosclerosis.
[http://en.wikipedia.org/wiki/LDL LDL particles] are constitued of a single apolipoprotein which is apo-B100. They are often called “bad cholesterol” because a high rate of LDL leads to a deposition of cholesterol as plaques on artery walls and that can causes cardiovascular problems.
 
Unlike to LDL,[http://en.wikipedia.org/wiki/High-density_lipoprotein HDL particles] are considered as “good cholesterol” because they are able to remove cholesterol, via the plasma, from peripheral tissues to the liver, where it will be degraded. They are constitued of apolipoproteins A-I and apo A-II. In fact, a high level of HDL can prevent from the accumulation of cholesterol in the plasma and avoid the developpement of cardiovascular diseases and atherosclerosis. That's why a promising solution to increase the level of HDL is the inhition of CETP.
HDL particles are considered as “good cholesterol” because they are able to remove cholesterol from peripheral tissues back to the liver via the plasma, in which they are degraded. This action prevents from the accumulation of cholesterol in the plasma.
Unlike to HDL, LDL particles are often called “bad cholesterol”. They enable the transport of cholesterol from its place of secretion into the cells of the body (within the bloodstream). A high rate of LDLs leads to the deposition of cholesterol as plaque on artery walls. This can result in cardiovascular problems.
Therefore, the inhibition of CETP could hinder the transport between HDL and LDL and so increases the HDL-C and decreases the VLDL-C. This action is a possible solution of atherosclerosis.


===Natural inhibitors===
===Natural inhibitors===


In the human plasma some natural inhibitors of CETP can be found: like Apo-F which suppresses the transfer involving LDL and Apo-CI, which his main role is to inhibit the CETP probably by altering the elecric charge of HDL.  
In the human plasma some natural inhibitors of CETP can be found: like Apo-CI, which his main role is to inhibit CETP, probably by altering the elecric charge of HDL.  


===Pharmaceutical inhibitors===
===Pharmaceutical inhibitors===


Pharmaceutical industrie tries to develop an inhibitor of CETP in order to decrease the risk of cardivascular diseases. The goal of these inhibitors is to increase the concentration of HDL and decrease the concentration of LDL by blocking CETP. Several inhibitors were found. The first was Torcetrapib followed by Anacetrapib, Dalcetrapib and the last one Evacetrapib.
The pharmaceutical industry tries to develop inhibitors of CETP in order to decrease the risk of cardivascular diseases. The goal of these inhibitors is to increase the concentration of HDL and decrease the concentration of LDL by blocking cholesteryl esters and triglyceride tranfer. Several inhibitors were found. The first was Torcetrapib followed by Anacetrapib, Dalcetrapib and the last one is Evacetrapib.
Torcetrapib succeeds in increasing the level of HDL, but his action develops side effects such as an increase of the blood pressure and the concentration of Sodium, Bicarbonate and aldosterone. That causes the death of many persons at the stage-III of the clinical trial. That's why this inhibitor was abort.
Torcetrapib succeeds in increasing the level of HDL, but his action has some side effects such as increasingthe blood pressure and the concentration of sodium, bicarbonate and aldosterone. That causes the death of many persons at the stage-III of the clinical trial. That's why this inhibitor was abort.
Unlike to torcetrapib, the other do not present any side effect for the moment, but still are in clinical trial. Evacetrapib seems to give the more promising results.
Unlike to torcetrapib, the other do not present any side effect, but they still are in clinical trial. Evacetrapib seems to give the more promising results.
 


==External ressources==
==External ressources==
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