Cholesteryl esters transfer protein

Plasma lipid transfer proteins, which include the cholesteryl-ester-transfer-protein (CETP previously known as lipid transfer protein I, LTP-I) and the phospholipid-transfer-protein (PLTP previously known as lipid transfer protein II, LTP-II) mediate the transfer of lipids (cholesteryl esters, triglycerides and phospholipids) between lipoproteins present in human plasma. These proteins significantly affect plasma lipoprotein concentration and composition. 

Qiu X, Mistry A, Ammirati MJ et al (2007) Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 14 106-113... 

Apohpoproteins carry out several roles (1) they can form part of the stmcture of the hpoprotein, eg, apo B (2) they are enzyme cofactors, eg, C-11 for lipoprotein hpase, A-1 for lecithinicholesterol acyltransferase, or enzyme inhibitors, eg, apo A-11 and apo C-111 for lipoprotein hpase, apo C-1 for cholesteryl ester transfer protein and (3) they act as hgands for interaction with lipopro-... 

Cholesteryl Ester Transfer Protein Facilitates Transfer of Cholesteryl Ester From HDL to Other Lipoproteins... 

Kuivenhoven JA, Jukema JW, Zwinder-man AH, de Knijff P, McPherson R, Bruschke AV, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998 338 86-93. 

Target genes involved in dmg response can also be involved in disease susceptibility. For example, polymorphisms of the cholesteryl ester transfer protein (CETP) are associated with both coronary atherosclerosis and response to pravastatin [22]. 

Korhonen T, FIannukseia ML, Seppa-nen S, Kervinen K, Kesaniemi YA, Sa-volainen MJ. The effect of the apolipo-protein E phenotype on cholesteryl ester transfer protein activity, plasma lipids and apolipoprotein A I levels in hyperch-olesterolaemic patients on colestipol and lovastatin treatment. Eur J Clin Pharmacol 1999 54 903-910. 

Ordovas JM, Cupples LA, Corella D, Otvos JD, Osgood D, Martinez A, et al. Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk the Framingham study. Arterioscler Thromb Vase Biol 2000 20 1323-1329. 

Freeman DJ, Wilson V, McMahon AD, Packard CJ, Gaffney D. A polymorphism of the Cholesteryl Ester Transfer Protein (CETP) gene predicts cardiovascular events in the West of Scotland Coronary... 

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). 

Terpstra, A. H. M., Lapre, J. A., de Vries, H. T., and Beynen, A. C. (1998). Dietary pectin with high viscosity lowers plasma and liver cholesterol concentration and plasma cholesteryl ester transfer protein activity in hamsters. /. Nutr. 128,1944-1949. 

Tabata N, Tomoda H, Omura S (1999) Ferroverdins, Inhibitors of Cholesteryl Ester Transfer Protein Produced by Streptomyces sp. WK-5344. II. Structure Elucidation. J Antibiotics 52 1108... 

Goff WL, Guerin M, Chapman JM. Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyshpidemia. Pharmacol Ther 2004 101 17-38. 

Brousseau ME, Schaefer EJ, Wolfe ML,etal. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004 350 1505-15. 

CA032 De Roos, B., A. Van Tol, R. Urgent, et al. Consumption of French-press coffee raises cholesteryl ester transfer protein activity levels before LDL cholesterol in normolipidemic subjects. J Intern Med 2000 248(3) 211-216. 

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not cause endocytosis of the lipoproteins. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

Dedecjus M, Masson D, Gautier T, de Barros JP, Gambert P, Lewinski A, Adamczewski Z, Moulin P, Lagrost L (2003) Low cholesteryl ester transfer protein (CETP) concentration but normal CETP activity in serum from patients with short-term hypothyroidism Lack of relationship to lipoprotein abnormalities. Clin Endocrinol (Oxf) 58 581-588... 

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... 

Mezdour H, Kora I, Parra HJ, Tartar A, Marcel YL, Fruchart JC (1994) Two-site enzyme immunoassay of cholesteryl ester transfer protein with monoclonal and oligoclonal antibodies. Clin Chem 40 593-597... 

---