Cholesterol ester transfer protein

High-density lipoproteins (HDL) have much longer life spans in the body (5 to 6 days) than other lipoproteins. Newly formed HDL contains virtually no cholesterol ester. However, over time, cholesterol esters are accumulated through the action of lecithin cholesterol acyltransferase (LCAT), a 59-kD glycoprotein associated with HDLs. Another associated protein, cholesterol ester transfer protein, transfers some of these esters to VLDL and LDL. Alternatively, HDLs function to return cholesterol and cholesterol esters to the liver. This latter process apparently explains the correlation between high HDL levels and reduced risk of cardiovascular disease. (High LDL levels, on the other hand, are correlated with an increased risk of coronary artery and cardiovascular disease.)... 

Under the same conditions, tricyclo[5.3.1.0]undecanes are accessible from 5-sub-stituted 2-cyclohexen-l-one as 2-370 with a shorter tether by one CH2-group. Recently, another Michael/Michael/aldol transformation was employed by Paulsen and coworkers to obtain access to the central aromatic core of compounds as 2-376 (Scheme 2.89) [206]. It is of value that such products are thought to act as cholesterol ester transfer protein (CETP) inhibitors, and the application of these drugs should prevent reduction of the HDL-cholesterol level and therefore reduce the risk of coronary heart diseases [207]. 

In 1998 the REGRESS group published data, which showed that the TaqlB polymorphism in intron 1 of the cholesterol-ester transfer protein (CETP) gene predicts whether men with coronary artery disease would benefit from treatment with pravastatin or not [60]. Pravastatin therapy slowed the progression of coronary athero-... 

Failure to respond to pravastatin (B2B2 variant of cholesterol ester transfer protein)... 

Cholesterol ester transfer protein (CETP) exchanges cholesterol ester (from HDL) with triglyceride (to HDL) and both lipoproteins may be cleared by the liver. 

LCAT, lecithin cholesterol acyltransferase CETP, cholesterol ester transfer protein SR-61, scavenger receptor-BI... 

HDL cholesterol picked up in the periphery can be distributed to other lipoprotein particles such as VLDL remnants (IDL), converting them to LDL. The cholesterol ester transfer protein facilitates this transfer, shotvn in Figure 1-15-6. 

Cholesterol ester transfer protein catalyses the transfer of triacylglycerol from VLDL or chylomicrons to LDL and to HDL. However, it is the removal of this triacylglycerol from LDL and HDL, which occurs in the liver, via hepatic lipase, that causes problems small and dense LDL particles, which are more atherogenic than normal... 

Choiesteryi Ester Transfer Protein inhibitors Cholesterol ester transfer protein (CETP) is a glycoprotein that transfers choiesteryi ester from HDL (high density lipoprotein) to proatherogenic apolipoproteins (LDL—(low density lipoprotein). Its inhibition has beneficial effects at the level of HDL cholesterol. SC-71952 and torcetrapib are highly fluorinated CETP inhibitors. SC-71952 is a disymmetrical sulfide with 10 fluorine atoms. Torcetrapib contains three CF3 groups (Figure 8.61). ... 

HV Kothari, KJ Poirier, WH Lee, Y Satoh. Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters. Atherosclerosis 128 59-66, 1997. 

The nascent HDL particles change shape and composition as they acquire additional free cholesterol by passive cellular diffusion of free cholesterol from cell membranes or from other plasma lipoproteins. HDL surface-localized LCAT progressively converts the free cholesterol on the surface of the particles to cholesterol ester, which occupies the core of the lipoprotein particle. This process converts the shape of the HDL particles from discoidal to spherical. The lipid unloading of HDL in the liver follows at least two pathways. In the first route, the cholesterol ester transfer protein (CETP) mediates cholesterol ester transfer from HDL to VLDL and LDL in exchange for triglyceride LDL in turn are taken up by the liver via the LDL receptor. In the second route, HDL binds to the scavenger receptor Bl, and cholesterol esters are selectively taken into the liver cells without internalization of HDL proteins (Fig. 15-2). 

The cholesterol esters of HDLs can also be transferred to VLDLs and LDLs through the action of the HDL-associated enzyme, cholesterol ester transfer protein (CETP). This has the added effect of allowing the excess cellular cholesterol to be returned to the liver through the LDL-receptor pathway as well as the HDL-receptor pathway. 

Jimenez F. Low-fat and high-monounsaturated fatty acid diets decrease plasma cholesterol ester transfer protein concentrations in young, healthy, normolipemic men. Am. J. Clin. Nutr. 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Kelkar, M.A., Pednekar, D.V., Pimple, S.R. and Akamanchi, K.G. (2004) 3D QSAR studies of inhibitors of cholesterol ester transfer protein (CETP) by CoMFA. CoMSlA and GFA methodologies. Med. Chem. Res., 13, 590-604. 

Apo D is a polypeptide found in HDLs (Table 18.1). Apo D is also called cholesterol ester transfer protein. 

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