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Gene Review

CETP  -  cholesteryl ester transfer protein, plasma

Homo sapiens

Synonyms: BPIFF, Cholesteryl ester transfer protein, HDLCQ10, Lipid transfer protein I
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Disease relevance of CETP

  • CETP gene expression is upregulated in response to increased dietary cholesterol or endogenous hypercholesterolemia [1].
  • In conclusion, rIFN-alpha2a treatment on patients with chronic hepatitis C causes marked changes in serum lipoprotein metabolism associated with decreases in LPL, HTGL, and CETP activities [2].
  • Recent data indicate that genetic CETP deficiency is associates with an excess of coronary heart disease in humans, despite increased HDL levels [3].
  • We examined the effects of 24-h hyperinsulinemia (30 mU x kg(-1) x h(-1)) and 24-h Acipimox (250 mg/4 h) on plasma lipids as well as CETP and PLTP activities (measured with exogenous substrate assays) in eight healthy and eight type 2 diabetic subjects [4].
  • CETP activity, PLTP activity, and CET were measured in 195 type 1 diabetic subjects without renal failure and 194 nondiabetic control subjects of similar age (30-55 years) and sex distribution (50% female) [5].

Psychiatry related information on CETP


High impact information on CETP

  • The cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) are members of the lipid transfer/lipopolysaccharide binding gene family [1].
  • The CETP plays a central role in reverse cholesterol transport i.e. the centripetal movement of cholesterol from the periphery back to the liver [1].
  • The CETP contains binding sites for cholesteryl ester and triglycerides and probably acts by a carrier-mediated mechanism [1].
  • RESULTS: The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [+/-SD], 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34+/-8 vs. 39+/-10 mg per deciliter) [10].
  • CONCLUSIONS: There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes [10].

Chemical compound and disease context of CETP

  • This study was designed to define the role of CETP and LCAT activities on HDL-cholesterol (HDL-C) plasma levels and HDL size distribution, as determined by nondenaturating polyacrylamide gradient gel electrophoresis in 47 clinically healthy Mexican individuals without personal and family history of coronary heart disease [11].
  • We found that monensin treatment or energy depletion of the SW872 liposarcoma cells with 2-deoxyglucose and NaN3 had no effect on CETP-mediated selective uptake, demonstrating that endocytosis is not required [12].
  • Thus, genetic variation at the CETP gene locus may account for a significant proportion of the difference in HDL-C levels; however, it seems reasonable to suggest that the effects of the allele interact with genetic variations expressed within the sample population, and with sex, obesity, and plasma triglyceride levels [13].
  • We measured the plasma concentration of low density lipoprotein (LDL) subfractions (by density gradient ultracentrifugation), RLP (by immunoaffinity gel), very low density lipoprotein (VLDL) subfractions, post heparin lipases and cholesteryl ester transfer protein (CETP) activity in 27 patients with glomerular disease and albuminuria >2.0g [14].
  • These results indicate that the CETP promoter -1337C>T polymorphism is associated with the progression of coronary atherosclerosis in Japanese patients with FH, independent of HDL-C and triacylglycerol levels [15].

Biological context of CETP

  • To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis [16].
  • The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2 [16].
  • We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype [16].
  • CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect [16].
  • Using a partial amino-acid sequence from this purified protein, CETP complementary DNA derived from human liver DNA has been cloned and sequenced and the cloned DNA used to detect CETP messenger RNA in a number of human tissues [17].

Anatomical context of CETP


Associations of CETP with chemical compounds

  • Although CETP reduces HDL levels, its role in reverse cholesterol transport suggests a dominant anti-atherogenic action in vivo [1].
  • Spherical HDL are further remodelled by cholesteryl ester transfer protein (CETP) that transfers cholesteryl esters from HDL to other lipoproteins and by hepatic lipase that hydrolyses HDL triglyceride in processes that reduce HDL size and lead to the dissociation of prebeta-migrating, lipid-poor apolipoprotein (apo)A-I from the particle [20].
  • Addition of sodium oleate to VLDL and albumin resulted in stimulation of the CETP-mediated transfer of cholesteryl esters from HDL to VLDL [21].
  • Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice [22].
  • Lag time for LDL and HDL in both cases became prolonged more than 1.8 times after administration of probucol.This study demonstrated for the first time that probucol reduces HDL-C even in humans with complete CETP deficiency [23].
  • Relatively high plasma CETP may favour reduced CVD risk in the context of low triglycerides [24].

Physical interactions of CETP

  • Lipolysis of apoprotein-free phospholipid/triglyceride emulsions also resulted in enhanced binding of CETP to the emulsion particles [21].
  • In vitro lipoprotein lipase enhances the cholesteryl ester transfer protein (CETP)-mediated transfer of cholesteryl esters from high density lipoproteins (HDL) to very low density lipoproteins as a result of lipolysis-induced alterations in lipoprotein lipids that lead to increased binding of CETP [25].
  • These data indicated that the apo E-rich HDL in CETP-deficient human subjects contained multiple copies of apo E and bound to the LDL receptor through multiple interactions [26].
  • We have putatively denoted this region, the cholesterol response element (CRE).Using gel mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the CRE of CETP [27].
  • These artificial fusions retain BPI functions such as lipopolysaccharide (LPS) binding and protein-protein interactions that are not observed with native CETP [28].

Enzymatic interactions of CETP

  • RNase protection analysis of tissue RNA confirmed the presence of exon 9 deleted transcripts and showed that they represented a variable proportion of the total CETP mRNA in various human tissues including adipose tissue (25%), liver (33%), and spleen (46%) [29].

Regulatory relationships of CETP

  • CETP activity was influenced by race and PLTP by age [30].
  • These experiments show that LPL enhances the CETP-mediated transfer of cholesteryl esters from HDL to VLDL [31].
  • Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice [32].
  • This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency [33].
  • Although LTIP inhibits CETP activity among different lipoprotein classes, it preferentially suppresses transfer events involving low density lipoprotein (LDL), whereas transfers involving high density lipoprotein as donor are less affected [34].

Other interactions of CETP

  • By stepwise regression analysis CETP appeared to contribute 15.2% and LCAT 9.8% to variation in HDL-cholesterol levels [35].
  • HL (P < 0.05) and CETP activities (P < 0.05) were elevated in hyperthyroidism and reduced in hypothyroidism (P < 0.05, P < 0.01 respectively) and both were related to free T4 levels [36].
  • The present study was performed to define the roles of lipolytic enzymes (hepatic and lipoprotein lipase) and cholesteryl ester transfer protein (CETP) in determining the distribution of LDL subfractions in these patients [37].
  • The present study demonstrates that the CETP Msp1 and Apo E gene polymorphisms are associated with variations in lipids in patients with CAD and healthy controls in Turkish population [38].
  • APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort) [39].

Analytical, diagnostic and therapeutic context of CETP


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  2. Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Shinohara, E., Yamashita, S., Kihara, S., Hirano, K., Ishigami, M., Arai, T., Nozaki, S., Kameda-Takemura, K., Kawata, S., Matsuzawa, Y. Hepatology (1997) [Pubmed]
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  4. Plasma phospholipid transfer protein activity is lowered by 24-h insulin and acipimox administration: blunted response to insulin in type 2 diabetic patients. Riemens, S.C., van Tol, A., Sluiter, W.J., Dullaart, R.P. Diabetes (1999) [Pubmed]
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  9. No physical activity x CETP 1b.-629 interaction effects on lipid profile. Bernstein, M.S., Costanza, M.C., James, R.W., Morris, M.A., Cambien, F., Raoux, S., Morabia, A. Medicine and science in sports and exercise. (2003) [Pubmed]
  10. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. Kuivenhoven, J.A., Jukema, J.W., Zwinderman, A.H., de Knijff, P., McPherson, R., Bruschke, A.V., Lie, K.I., Kastelein, J.J. N. Engl. J. Med. (1998) [Pubmed]
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  12. Role of cholesteryl ester transfer protein in selective uptake of high density lipoprotein cholesteryl esters by adipocytes. Vassiliou, G., McPherson, R. J. Lipid Res. (2004) [Pubmed]
  13. Genetic variations in the cholesteryl ester transfer protein gene and high density lipoprotein cholesterol levels in Taiwanese Chinese. Hsu, L.A., Ko, Y.L., Hsu, K.H., Ko, Y.H., Lee, Y.S. Hum. Genet. (2002) [Pubmed]
  14. The atherogenic lipoprotein phenotype: small dense LDL and lipoprotein remnants in nephrotic range proteinuria. Deighan, C.J., Caslake, M.J., McConnell, M., Boulton-Jones, J.M., Packard, C.J. Atherosclerosis (2001) [Pubmed]
  15. CETP (cholesteryl ester transfer protein) promoter -1337 C>T polymorphism protects against coronary atherosclerosis in Japanese patients with heterozygous familial hypercholesterolaemia. Takata, M., Inazu, A., Katsuda, S., Miwa, K., Kawashiri, M.A., Nohara, A., Higashikata, T., Kobayashi, J., Mabuchi, H., Yamagishi, M. Clin. Sci. (2006) [Pubmed]
  16. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. Inazu, A., Brown, M.L., Hesler, C.B., Agellon, L.B., Koizumi, J., Takata, K., Maruhama, Y., Mabuchi, H., Tall, A.R. N. Engl. J. Med. (1990) [Pubmed]
  17. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Drayna, D., Jarnagin, A.S., McLean, J., Henzel, W., Kohr, W., Fielding, C., Lawn, R. Nature (1987) [Pubmed]
  18. Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. Jiang, X.C., Moulin, P., Quinet, E., Goldberg, I.J., Yacoub, L.K., Agellon, L.B., Compton, D., Schnitzer-Polokoff, R., Tall, A.R. J. Biol. Chem. (1991) [Pubmed]
  19. Opposite effects of cholesteryl ester transfer protein and phospholipid transfer protein on the size distribution of plasma high density lipoproteins. Physiological relevance in alcoholic patients. Lagrost, L., Athias, A., Herbeth, B., Guyard-Dangremont, V., Artur, Y., Paille, F., Gambert, P., Lallemant, C. J. Biol. Chem. (1996) [Pubmed]
  20. Hugh sinclair lecture: the regulation and remodelling of HDL by plasma factors. Barter, P.J. Atherosclerosis. Supplements. (2002) [Pubmed]
  21. Mechanisms of enhancement of cholesteryl ester transfer protein activity by lipolysis. Sammett, D., Tall, A.R. J. Biol. Chem. (1985) [Pubmed]
  22. Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice. Kako, Y., Massé, M., Huang, L.S., Tall, A.R., Goldberg, I.J. J. Lipid Res. (2002) [Pubmed]
  23. Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency. Noto, H., Kawamura, M., Hashimoto, Y., Satoh, H., Hara, M., Iso-o, N., Togo, M., Kimura, S., Tsukamoto, K. Atherosclerosis (2003) [Pubmed]
  24. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Borggreve, S.E., Hillege, H.L., Dallinga-Thie, G.M., de Jong, P.E., Wolffenbuttel, B.H., Grobbee, D.E., van Tol, A., Dullaart, R.P. Eur. Heart J. (2007) [Pubmed]
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  26. Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. Yamashita, S., Sprecher, D.L., Sakai, N., Matsuzawa, Y., Tarui, S., Hui, D.Y. J. Clin. Invest. (1990) [Pubmed]
  27. Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1. Gauthier, B., Robb, M., Gaudet, F., Ginsburg, G.S., McPherson, R. J. Lipid Res. (1999) [Pubmed]
  28. Protein Fusions of BPI with CETP Retain Functions Inherent to Each. Lloyd, D.B., Bonnette, P., Thompson, J.F. Biochemistry (2006) [Pubmed]
  29. Alternative splicing of the mRNA encoding the human cholesteryl ester transfer protein. Inazu, A., Quinet, E.M., Wang, S., Brown, M.L., Stevenson, S., Barr, M.L., Moulin, P., Tall, A.R. Biochemistry (1992) [Pubmed]
  30. Moderate hyperalphalipoproteinaemia in a Brazilian population is related to lipoprotein lipase activity, apolipoprotein A-I concentration, age and body mass index. Alarcon, S.B., Oliveira, H.C., Harada, L.M., Nunes, V.S., Kaplan, D., Quintão, E.C., de Faria, E.C. Clin. Sci. (2004) [Pubmed]
  31. Lipoprotein lipase enhances the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from high density lipoproteins to very low density lipoproteins. Tall, A.R., Sammett, D., Vita, G.M., Deckelbaum, R., Olivecrona, T. J. Biol. Chem. (1984) [Pubmed]
  32. Apolipoprotein CI overexpression is not a relevant strategy to block cholesteryl ester transfer protein (CETP) activity in CETP transgenic mice. Gautier, T., Masson, D., Jong, M.C., Pais de Barros, J.P., Duverneuil, L., Le Guern, N., Deckert, V., Dumont, L., Bataille, A., Zak, Z., Jiang, X.C., Havekes, L.M., Lagrost, L. Biochem. J. (2005) [Pubmed]
  33. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. Ikewaki, K., Nishiwaki, M., Sakamoto, T., Ishikawa, T., Fairwell, T., Zech, L.A., Nagano, M., Nakamura, H., Brewer, H.B., Rader, D.J. J. Clin. Invest. (1995) [Pubmed]
  34. Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F. Wang, X., Driscoll, D.M., Morton, R.E. J. Biol. Chem. (1999) [Pubmed]
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  36. Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. Tan, K.C., Shiu, S.W., Kung, A.W. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  37. Roles of hepatic lipase and cholesteryl ester transfer protein in determining low density lipoprotein subfraction distribution in Chinese patients with non-insulin-dependent diabetes mellitus. Tan, K.C., Shiu, S.W., Chu, B.Y. Atherosclerosis (1999) [Pubmed]
  38. Cholesterol ester transfer protein, apolipoprotein E and lipoprotein lipase genotypes in patients with coronary artery disease in the Turkish population. Isbir, T., Yilmaz, H., Agachan, B., Karaali, Z.E. Clin. Genet. (2003) [Pubmed]
  39. APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort). Pallaud, C., Sass, C., Zannad, F., Siest, G., Visvikis, S. Clin. Genet. (2001) [Pubmed]
  40. Cholesteryl ester transfer protein mediates selective uptake of high density lipoprotein cholesteryl esters by human adipose tissue. Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R., McPherson, R. J. Biol. Chem. (1997) [Pubmed]
  41. Phospholipid transfer protein is present in human tear fluid. Jauhiainen, M., Setälä, N.L., Ehnholm, C., Metso, J., Tervo, T.M., Eriksson, O., Holopainen, J.M. Biochemistry (2005) [Pubmed]
  42. Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP levels. Kimura, H., Miyazaki, R., Imura, T., Masunaga, S., Suzuki, S., Gejyo, F., Yoshida, H. Kidney Int. (2003) [Pubmed]
  43. Organization of the human cholesteryl ester transfer protein gene. Agellon, L.B., Quinet, E.M., Gillette, T.G., Drayna, D.T., Brown, M.L., Tall, A.R. Biochemistry (1990) [Pubmed]
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