Sandbox 215: Difference between revisions

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Bleu Mélusine

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 == Mechanism allowing neutral-lipid and phospholipid transfer <ref name="rasmol" /> <ref name="rasmol1">James A Hamilton & Richard J Deckelbaum. Crystal structure of CETP: new hopes for raising HDL to decrease risk of cardiovascular disease? Nature Structural & Molecular Biology 14, 95 - 97 (2007). [https://www-ncbi-nlm-nih-gov.scd-rproxy.u-strasbg.fr/pubmed/17277799 PMID: 17277799] [http://www.nature.com.scd-rproxy.u-strasbg.fr/nsmb/journal/v14/n2/full/nsmb0207-95.html doi:10.1038/nsmb0207-95]</ref>==
-In the plasma circulation, CETP often binds high density lipoproteins (HDL) and engages the tranfer of neutral lipids, such as cholesteryl ester and triglyceride among lipoprotein particles. The concave structure of CETP is the only surface able to bind a lipoprotein. Other surfaces of CETP are not able to bind them. It indicates that CETP can only bind one lipoprotein at a time. It means that CETP operates as carrier: CETP accepts neutral lipids from a donor particule and releases them to an acceptor particule.
+In the plasma, CETP often binds high density lipoproteins (HDL) and engages the tranfer of neutral lipids, such as cholesteryl ester and triglyceride among lipoprotein particles. The concave structure of CETP is the only surface able to bind a lipoprotein. Other surfaces of CETP are not able to bind them. It indicates that CETP can only bind one lipoprotein at a time. It means that CETP operates as carrier: CETP accepts neutral lipids from a donor particule and releases them to an acceptor particule.
-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 phospholipids (one at each end) that permits the protein to dissociate from HDL and to return 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 and to permit the release of the bound phospholipid. Then 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 phospholipids (one at each end) that permit the protein to dissociate from HDL and to return 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 and to permit the release of the bound phospholipid. Then the cycle can continue.
 ==CETP inhibition <ref name="rasmol1" />==
-[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.
+[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 deposit of cholesterol as plaques in arteries and that can cause 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.
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 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 is Torcetrapib followed of Anacetrapib, Dalcetrapib and Evacetrapib.
-Torcetrapib was developed by Pfizer in order to treat hypercholesterolemia (high cholesterol levels) and prevent [http://en.wikipedia.org/wiki/Atherosclerosis atherosclerosis]. Torcetrapib managed to reduce CETP activity and succeeds in increasing the level of HDL. However, in stage-III clinical trials, Torcetrapib causes significant changes in vital signs: like increases the blood pressure, the concentration of sodium, bicarbonate and aldosterone.  The explanations for this unexpected result remain unclear. Maybe increased binding of torcetrapib-CETP complexes to HDL interferes with some of the anti-cardiovascular diseases (anti-CVD) activity of HDL causing the death of many persons. That's why, in 2006, this inhibitor was halted.
+Torcetrapib was developed by Pfizer in order to treat hypercholesterolemia (high cholesterol levels) and prevent [http://en.wikipedia.org/wiki/Atherosclerosis atherosclerosis]. Torcetrapib managed to reduce CETP activity and succeeds in increasing the level of HDL. However, in stage-III clinical trials, Torcetrapib causes significant changes in vital signs: like increases the blood pressure, the concentration of sodium, bicarbonate and aldosterone.  The explanations for this unexpected result remain unclear but perhaps increased binding of torcetrapib-CETP complexes to HDL may interfer with the anti-cardiovascular diseases (anti-CVD) activity of HDL causing the death of many persons. That's why, in 2006, this inhibitor was halted.
 Unlike to Torcetrapib, the other which still are in clinical trial do not have any side effects.