Cholesterylester transfer protein

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Cholesteryl ester transfer protein, plasma
Protein CETP PDB 2obd.png
PDB rendering based on 2obd.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CETP ; BPIFF; HDLCQ10
External IDs OMIM118470 HomoloGene47904 ChEMBL: 3572 GeneCards: CETP Gene
RNA expression pattern
PBB GE CETP 206210 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1071 n/a
Ensembl ENSG00000087237 n/a
UniProt P11597 n/a
RefSeq (mRNA) NM_000078 n/a
RefSeq (protein) NP_000069 n/a
Location (UCSC) Chr 16:
57 – 57.02 Mb
n/a
PubMed search [1] n/a

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

Genetics[edit]

The CETP gene is located on the sixteenth chromosome (16q21).

Role in disease[edit]

Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[1] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [2] and to metabolic response to nutritional intervention.[3] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[4] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[1]

Elaidic acid, a major component of trans fat, increases CETP activity.[5]

Pharmacology[edit]

See also: CETP inhibitor

As HDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.[6] To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin, and lower LDL when co-administered with a statin.[7] Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis,[8][9] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[10]

A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also being studied, but trials have since been ceased.[11] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[12] Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies is not shown to increase blood pressure.[13]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin_Pathway_WP430 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article
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  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

References[edit]

  1. ^ a b Zhong S, Sharp D, Grove J, Bruce C, Yano K, Curb J et al. (June 1996). "Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels". J Clin Invest 97 (12): 2917–23. doi:10.1172/JCI118751. PMC 507389. PMID 8675707. 
  2. ^ Barzilai N, Atzmon G, Schechter C, Schaefer E, Cupples A, Lipton R et al. (October 2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA 290 (15): 2030–40. doi:10.1001/jama.290.15.2030. PMID 14559957. 
  3. ^ Darabi M, Abolfathi A, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A et al. (2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Horm Metab Res 41 (7): 554–8. doi:10.1055/s-0029-1192034. PMID 19242900. 
  4. ^ Bruce C, Sharp D, Tall A (1 May 1998). "Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia". J Lipid Res 39 (5): 1071–8. PMID 9610775. 
  5. ^ Abbey M, Nestel P (March 1994). "Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet". Atherosclerosis 106 (1): 99–107. doi:10.1016/0021-9150(94)90086-8. PMID 8018112. 
  6. ^ Barter P, Brewer H, Chapman M, Hennekens C, Rader D, Tall A (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arterioscler Thromb Vasc Biol 23 (2): 160–7. doi:10.1161/01.ATV.0000054658.91146.64. PMID 12588754. 
  7. ^ Brousseau M, Schaefer E, Wolfe M, Bloedon L, Digenio A, Clark R et al. (April 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". N Engl J Med 350 (15): 1505–15. doi:10.1056/NEJMoa031766. PMID 15071125. 
  8. ^ Nissen S, Tardif J, Nicholls S, Revkin J, Shear C, Duggan W et al. (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med 356 (13): 1304–16. doi:10.1056/NEJMoa070635. ISSN 0028-4793. PMID 17387129. 
  9. ^ Kastelein J, van Leuven S, Burgess L, Evans G, Kuivenhoven J, Barter P et al. (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". N Engl J Med 356 (16): 1620–30. doi:10.1056/NEJMoa071359. PMID 17387131. 
  10. ^ "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety" (Press release). U.S. Food and Drug Administration. 2006-12-03. 
  11. ^ El Harchaoui K, van der Steeg W, Stroes E, Kastelein J (August 2007). "The role of CETP inhibition in dyslipidemia". Curr Atheroscler Rep 9 (2): 125–33. doi:10.1007/s11883-007-0008-5. PMID 17877921. 
  12. ^ de Grooth G, Kuivenhoven J, Stalenhoef A, de Graaf J, Zwinderman A, Posma J et al. (May 2002). "Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study". Circulation 105 (18): 2159–65. doi:10.1161/01.CIR.0000015857.31889.7B. PMID 11994249. 
  13. ^ Reuters (2007-10-04). "Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes". Reuters, Inc. Retrieved 26 November 2013. 

Further reading[edit]

External links[edit]