Cholesteryl ester transfer protein inhibition

Forrester JS, Makkar R, Shah PK (2005) Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition an update for clinicians. Circulation 111 1847-1854... 

CL Bisgaier, AD Essenburg, LL Minton, R Homan, CJ Blankley, A White. Cholesteryl ester transfer protein inhibition by PD 140195. Lipids 29 811—818, 1994. 

When used in conjunction with niacin or niceritol, Sikorski (4) determined that the benzyl amine cholesteryl ester transfer protein inhibiting agent, (III), was effective in treating atherosclerosis. 

The recent years have seen the success of statins like Lipitor (atorvastatin) as hypolipidemic agents that help treating cardiovascular disease primarily by lowering low-density lipoproteins ( bad cholesterol ) levels. Another novel strategy is to tackle the same problem by elevating high-density lipoproteins (H D L or good cholesterol ) levels via inhibition of cholesteryl ester transfer protein (CETP). 

Tomoda H, Matsushima C, Tabata N, Namatame I, Tanaka H, Bamberger MJ, Arai H, Fukazawa M, Inoue K, Omura S (1999) Structure-Specific Inhibition of Cholesteryl Ester Transfer Protein by Azaphilones. J Antibiot 52 160... 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

Tchoua, U., D Souza, W., Mukhamedova, N., Blum, D., Niesor, E., Mizrahi, J., Maugeais, C., Sviridov, D. (2008 The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport. Cardiovasc. Res. 77, 732-739. 

H Tomoda, C Matsushima, N Tabata, I Namatame, H Tanaka, H Arai, M Fukazawa, K Inoue, S Omura. Structure-specific inhibition of cholesteryl ester transfer protein by azaphilones. J Antibiot 52 160-170, 1999. 

DE Epps, KA Greenlee, JS Harris, EW Thomas, CK Castle, JF Fisher, RR Hozak, CK Marschke, GW Melchior, FL Kezdy. Kinetics and inhibition of lipid exchange catalyzed by plasma cholesteryl ester transfer protein (lipid transfer protein). Biochemistry 34 12560-12569, 1995. 

KH Cho, JY Lee, MS Choi, JM Cho, JS Lim, YB Park. A peptide from hog plasma that inhibits human cholesteryl ester transfer protein. Biochim Biophys Acta 1391 133-144, 1998. 

N Tabata, H Tomoda, Y Yamaguchi, R Masuma, MJ Bamberger, S Omura. Inhibition of cholesteryl ester transfer protein by fungal L681,512 compounds. J Antibiot 52 1042-1045, 1999. 

H Kotake, LB Agellon, S Yokoyama. Modification of the N-terminal cysteine of plasma cholesteryl ester transfer protein selectively inhibits triglyceride transfer activity. Biochim Biophys Acta 1347 69-74, 1997. 

Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader 146. DJ, Tall AR. Cholesteryl ester transfer protein a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. 

Clark RW, Sutfin TA, Rugged RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein An initial multidose study of torcetrapib. Arterioscler Thromb Vase Biol 2004 24 490-497. 

The compound 19 also inhibited the activity of cholesteryl ester transfer protein (CETP) with an IC50 value of 98 pM. The compounds 18, 20 and 21 weakly inhibited the activity of CETP in 300 pM. 

Decreases in plasma VLDL primarily result from the ability of these compounds to stimulate the activity of lipoprotein lipase, the enzyme responsible for removing triglycerides from plasma VLDL (Fig. 30.5). Additionally, fibrates can lower VLDL levels through PPARa-mediated stimulation of fatty acid oxidation, inhibition of triglyceride synthesis, and reduced expression of apoC-lll. This latter effect enhances the action of lipoprotein lipase, because apoC-lll normally serves as an inhibitor of this enzyme. Favorable effects on FIDL levels appear to be related to increased transcription of apoA-l and apoA-ll as well as a decreased activity of cholesteryl ester transfer protein. 

Qin Y, Xia M, Ma J, Hao Y, Liu J, Mou H, Cao L, ling W (2009) Anthocyanin supplementation improves serum LDL- and HDL-cholestool conciaitratiivis associated with the inhibition of cholesteryl ester transfer protein in dysli ndemic subjects. Am J Qin Nutr 90 485-492... 

As mentioned earlier, decreased HDL-C levels constitute a major risk factor for CAD and LEAD. A novel therapeutic approach to raise HDL is inhibition of cholesteryl ester transfer protein (CETP) (123). Individuals with CETP deficiency as a result of molecular defects in the CETP gene, have markedly elevated plasma levels of HDL-C and apoli-poprotein A-I (124). 

Inhibition of cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL particles and other lipoprotein fractions to atherogenic apo B-containing lipoproteins, leads to a substantial increase in HDL-Cconcentrations and also reduces LDL-C concentrations. Torcetrapib, the first CETP inhibitor evaluated in phase III clinical trials, caused increases in all-cause mortality and cardiovascular events, despite a dramatic increase in HDL-C concentrations. This paradox was explained by stimulation of aldosterone production, leading to increased blood pressure and low serum potassium [23]. Consequently, the large clinical outcomes trial, ILLUMINATE, was prematurely terminated in 2006. 

This protein is found in plasma of humans and many other species, associated with HDL. It facilitates transfer of cholesteryl ester from HDL to VLDL, IDL, and LDL in exchange for triacylglycerol, relieving product inhibition of LCAT activity in HDL. Thus, in humans, much of the cholesteryl ester formed by LCAT finds its way to the hver via VLDL remnants (IDL) or LDL (Figure 26-6). The triacylglycerol-enriched HDL2 delivers its cholesterol to the hver in the HDL cycle (Figure 25-5). 

Figure 7.64 Inhibition of the protein of transfer of cholesteryl esters (CEPT) by fluorinated amino...

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