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{{PBB_Controls
{{Infobox_gene}}
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'''Cholesteryl ester transfer protein''' ('''CETP'''), also called '''plasma lipid transfer protein''', is a [[blood plasma|plasma]] [[protein]] that facilitates the transport of [[cholesteryl ester]]s and [[triglyceride]]s between the [[lipoprotein]]s. It collects triglycerides from [[Very-low-density lipoprotein|very-low-density]] (VLDL) or [[low-density lipoprotein]]s (LDL) and exchanges them for cholesteryl esters from [[high-density lipoprotein]]s (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.
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{{GNF_Protein_box
| image = PBB_Protein_CETP_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2obd.
| Name = Cholesteryl ester transfer protein, plasma
| HGNCid = 1869
| Symbol = CETP
| AltSymbols =;
| OMIM = 118470
| ECnumber = 
| Homologene = 47904
| MGIid = 
| GeneAtlas_image1 = PBB_GE_CETP_206210_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003824 |text = catalytic activity}} {{GNF_GO|id=GO:0008289 |text = lipid binding}}
| Component =
| Process = {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006869 |text = lipid transport}} {{GNF_GO|id=GO:0008202 |text = steroid metabolic process}} {{GNF_GO|id=GO:0008203 |text = cholesterol metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1071
    | Hs_Ensembl = ENSG00000087237
    | Hs_RefseqProtein = NP_000069
    | Hs_RefseqmRNA = NM_000078
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 55553263
    | Hs_GenLoc_end = 55575257
    | Hs_Uniprot = P11597
    | Mm_EntrezGene = 
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = 
    | Mm_RefseqProtein = 
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end =
    | Mm_Uniprot = 
  }}
}}
{{CMG}}
 
==Overview==
Cholesteryl ester transfer protein (CETP) (also called plasma lipid transfer protein) is a [[blood plasma|plasma]] [[protein]] that facilitates the transport of [[cholesteryl ester]]s and [[triglyceride]]s between the [[lipoprotein]]s. It collects triglycerides from [[Very low density lipoprotein|very low density]] or [[low density lipoprotein]]s (VLDL or LDL) and exchanges them for cholesteryl esters from [[high density lipoprotein]]s (and vice versa). Most of the time, however, CETP does a homoexchange- trading a triglyceride for a triglyceride or a cholesteryl ester for a cholesteryl ester.


==Genetics==
==Genetics==
The ''CETP'' gene is located on the sixteenth [[chromosome]] (16q21).
The ''CETP'' gene is located on the sixteenth [[chromosome]] (16q21).
== Protein Fold ==
The [[crystal structure]] of CETP is that of [[Dimer (chemistry)|dimer]] of two [[TUbular LIPid (TULIP)]] binding domains.<ref>{{cite journal | vauthors = Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP | title = Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 2 | pages = 106–13 | date = February 2007 | pmid = 17237796 | doi = 10.1038/nsmb1197 }}</ref><ref>{{cite journal | vauthors = Alva V, Lupas AN | title = The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport | journal = Biochimica et Biophysica Acta | volume = 1861 | issue = 8 Pt B | pages = 913–923 | date = August 2016 | pmid = 26825693 | doi = 10.1016/j.bbalip.2016.01.016 }}</ref> Each domain consists of a core of 6 elements: 4 [[Beta sheet|beta-sheets]] forming an extended superhelix; 2 flanking elements that tend to include some [[alpha helix]]. The sheets wrap around the helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 [[Beta sheet|beta-sheets]], 3 from each [[protomer]]. The same fold is shared by Bacterial Permeability Inducing proteins (examples: [[BPIFB1|BPIFP1]] [[BPI fold-containing family B member 2|BPIFP2]] [[BPIFA3]] and [[BPIFB4]]), phospholipid transfer protein ([[PLTP|PLTP)]], and long-Palate Lung, and Nasal Epithelium protein [[Plunc|(L-PLUNC)]]. The fold is similar to intracellular SMP domains,<ref>{{cite journal | vauthors = Reinisch KM, De Camilli P | title = SMP-domain proteins at membrane contact sites: Structure and function | journal = Biochimica et Biophysica Acta | volume = 1861 | issue = 8 Pt B | pages = 924–927 | date = August 2016 | pmid = 26686281 | pmc = 4902782 | doi = 10.1016/j.bbalip.2015.12.003 }}</ref> and originated in bacteria.<ref>{{cite journal | vauthors = Wong LH, Levine TP | title = Tubular lipid binding proteins (TULIPs) growing everywhere | journal = Biochimica et Biophysica Acta | volume = 1864 | issue = 9 | pages = 1439–1449 | date = September 2017 | pmid = 28554774 | pmc = 5507252 | doi = 10.1016/j.bbamcr.2017.05.019 }}</ref><ref>{{cite journal | vauthors = Lam KH, Qi R, Liu S, Kroh A, Yao G, Perry K, Rummel A, Jin R | title = The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein | journal = Toxicon | volume = 147 | pages = 19–26 | date = June 2018 | pmid = 29042313 | pmc = 5902665 | doi = 10.1016/j.toxicon.2017.10.012 }}</ref><ref>{{cite journal | vauthors = Gustafsson R, Berntsson RP, Martínez-Carranza M, El Tekle G, Odegrip R, Johnson EA, Stenmark P | title = Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster | journal = FEBS Letters | volume = 591 | issue = 22 | pages = 3781–3792 | date = November 2017 | pmid = 29067689 | doi = 10.1002/1873-3468.12889 }}</ref> The crystal structure of CETP has been obtained with bound [[CETP Inhibitors|CETP inhibitors]].<ref>{{cite journal | vauthors = Liu S, Mistry A, Reynolds JM, Lloyd DB, Griffor MC, Perry DA, Ruggeri RB, Clark RW, Qiu X | title = Crystal structures of cholesteryl ester transfer protein in complex with inhibitors | journal = The Journal of Biological Chemistry | volume = 287 | issue = 44 | pages = 37321–9 | date = October 2012 | pmid = 22961980 | pmc = 3481329 | doi = 10.1074/jbc.M112.380063 }}</ref> However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.<ref>{{cite journal | vauthors = Lauer ME, Graff-Meyer A, Rufer AC, Maugeais C, von der Mark E, Matile H, D'Arcy B, Magg C, Ringler P, Müller SA, Scherer S, Dernick G, Thoma R, Hennig M, Niesor EJ, Stahlberg H | title = Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP | journal = Journal of Structural Biology | volume = 194 | issue = 2 | pages = 191–8 | date = May 2016 | pmid = 26876146 | doi = 10.1016/j.jsb.2016.02.016 }}</ref>


==Role in disease==
==Role in disease==
Rare mutations leading to increased function of CETP have been linked to accelerated [[atherosclerosis]].<ref name=Zhong1996>{{cite journal |author= Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR |year=1996 |month=Jun |title= Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels |journal=J Clin Invest |volume=97 |issue=12 |pages=2917-23 |id=PMID 8675707 |url=http://www.jci.org/cgi/content/full/97/12/2917}}</ref> In contrast, a polymorphism (I405V) of the ''CETP'' gene leading to lower serum levels has also been linked to exceptional longevity.<ref>{{cite journal |author=Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR |year= 2003|month=Oct |title=Unique lipoprotein phenotype and genotype associated with exceptional longevity |journal=JAMA |volume=290 |issue=15 |pages=2030-40 |id=PMID 14559957 |url=http://jama.ama-assn.org/cgi/content/full/290/15/2030}}</ref> However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.<ref>{{cite journal |author=Bruce C, Sharp DS, Tall AR |year=1998|month=May |title= |journal=J Lipid Res |volume=39 |issue=5 |pages=1071-8  |id=PMID 9610775 |url=http://www.jlr.org/cgi/content/full/39/5/1071}}</ref> The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.<ref name=Zhong1996/>
Rare mutations leading to reduced function of CETP have been linked to accelerated [[atherosclerosis]].<ref name=Zhong1996>{{cite journal | vauthors = Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR | title = Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels | journal = The Journal of Clinical Investigation | volume = 97 | issue = 12 | pages = 2917–23 | date = June 1996 | pmid = 8675707 | pmc = 507389 | doi = 10.1172/JCI118751 }}</ref> In contrast, a polymorphism (I405V) of the ''CETP'' gene leading to lower serum levels has also been linked to exceptional longevity <ref>{{cite journal | vauthors = Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR | title = Unique lipoprotein phenotype and genotype associated with exceptional longevity | journal = JAMA | volume = 290 | issue = 15 | pages = 2030–40 | date = October 2003 | pmid = 14559957 | doi = 10.1001/jama.290.15.2030 }}</ref> and to metabolic response to nutritional intervention.<ref name="pmid19242900">{{cite journal | vauthors = Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A, Darabi M, Ghatrehsamani K | title = Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition | journal = Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme | volume = 41 | issue = 7 | pages = 554–8 | date = July 2009 | pmid = 19242900 | doi = 10.1055/s-0029-1192034 }}</ref> However, this mutation also increases the prevalence of [[coronary heart disease]] in patients with [[hypertriglyceridemia]].<ref>{{cite journal | vauthors = Bruce C, Sharp DS, Tall AR | title = 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 | journal = Journal of Lipid Research | volume = 39 | issue = 5 | pages = 1071–8 | date = May 1998 | pmid = 9610775 }}</ref> The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.<ref name=Zhong1996/>


[[Elaidic acid]]&mdash;a major component of [[trans fat]]&mdash;increases CETP activity.<ref name="pmid8018112">{{cite journal |author=Abbey M, Nestel PJ |title=Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet |journal=Atherosclerosis |volume=106 |issue=1 |pages=99–107 |year=1994 |pmid=8018112|doi=10.1016/0021-9150(94)90086-8}}</ref>
[[Elaidic acid]], a major component of [[trans fat]], increases CETP activity.<ref name="pmid8018112">{{cite journal | vauthors = Abbey M, Nestel PJ | title = Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet | journal = Atherosclerosis | volume = 106 | issue = 1 | pages = 99–107 | date = March 1994 | pmid = 8018112 | doi = 10.1016/0021-9150(94)90086-8 }}</ref>


==Pharmacology==
==Pharmacology==
As [[High density lipoprotein|HDL]] has a protective function in atherosclerosis and [[cardiovascular disease]], and certain disease states (such as the [[metabolic syndrome]]) feature low HDL, pharmacological inhibition of CETP is being studied as a method to improve HDL levels.<ref>{{cite journal |author=Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR |year=2003 |month=Feb |title=Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis |journal=Arterioscler Thromb Vasc Biol |volume=23 |issue=2 |pages=160-7 |id=PMID 12588754 |url=http://atvb.ahajournals.org/cgi/content/full/23/2/160}}</ref> Specifically, 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) in a 2004 study.<ref>{{cite journal |author=Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ |year=2004 |month=Apr |title=Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol |journal=N Engl J Med |volume=350 |issue=15 |pages=1505-15 |id=PMID 15071125 |url=http://content.nejm.org/cgi/content/full/350/15/1505}}</ref> 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,<ref>{{cite journal |author=Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM; ILLUSTRATE Investigators |year=2007 |month=Mar |title=Effect of torcetrapib on the progression of coronary atherosclerosis |journal=N Engl J Med |volume=356 |issue=13 |pages=1304-16 |id=PMID 17387129 |url=http://content.nejm.org/cgi/content/full/356/13/1304}}</ref><ref>{{cite journal |author=Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML; RADIANCE 1 Investigators. |year=2007 |month=Apr |title=Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia |journal=N Engl J Med |volume=356 |issue=16 |pages=1620-30 |id=PMID 17387131 |url=http://content.nejm.org/cgi/content/abstract/356/16/1620}}</ref> and (in a trial of a combination of torcetrapib and atorvastatin) an increase in cardiovascular events and mortality.<ref name=FDA2006>{{cite press release |title=Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety |publisher=U.S. Food and Drug Administration |date=3 December 2006 |url=http://www.fda.gov/bbs/topics/news/2006/new01514.html}}</ref>
{{see also|CETP inhibitor}}
As [[High-density lipoprotein|HDL]] can alleviate atherosclerosis and other [[cardiovascular disease]]s, 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.<ref>{{cite journal | vauthors = Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR | title = Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 2 | pages = 160–7 | date = February 2003 | pmid = 12588754 | doi = 10.1161/01.ATV.0000054658.91146.64 }}</ref> 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.<ref>{{cite journal | vauthors = Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ | title = Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol | journal = The New England Journal of Medicine | volume = 350 | issue = 15 | pages = 1505–15 | date = April 2004 | pmid = 15071125 | doi = 10.1056/NEJMoa031766 }}</ref> 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,<ref>{{cite journal | vauthors = Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM | title = Effect of torcetrapib on the progression of coronary atherosclerosis | journal = The New England Journal of Medicine | volume = 356 | issue = 13 | pages = 1304–16 | date = March 2007 | pmid = 17387129 | doi = 10.1056/NEJMoa070635 | last11 = Illustrate | first11 = Investigators | deadurl = no }}</ref><ref>{{cite journal | vauthors = Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML | title = Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia | journal = The New England Journal of Medicine | volume = 356 | issue = 16 | pages = 1620–30 | date = April 2007 | pmid = 17387131 | doi = 10.1056/NEJMoa071359 }}</ref> and, in a trial of a combination of torcetrapib and [[atorvastatin]], an increase in cardiovascular events and mortality.<ref name=FDA2006>{{cite press release |title=Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety |publisher=U.S. Food and Drug Administration |date=2006-12-03 |url=http://www.fda.gov/bbs/topics/news/2006/new01514.html}}</ref>
 
A compound related to torcetrapib, [[Dalcetrapib]] (investigative name JTT-705/R1658), was also studied, but trials have ceased.<ref>{{cite journal | vauthors = El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ | title = The role of CETP inhibition in dyslipidemia | journal = Current Atherosclerosis Reports | volume = 9 | issue = 2 | pages = 125–33 | date = August 2007 | pmid = 17877921 | doi = 10.1007/s11883-007-0008-5 }}</ref> It increases HDL levels by 30%, as compared to 60% by torcetrapib.<ref>{{cite journal | vauthors = de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ | title = Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study | journal = Circulation | volume = 105 | issue = 18 | pages = 2159–65 | date = May 2002 | pmid = 11994249 | doi = 10.1161/01.CIR.0000015857.31889.7B }}</ref> Two CETP inhibitors were previously under development. One was Merck's MK-0859 [[anacetrapib]], which in initial studies did not increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url=https://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004 |publisher=Reuters, Inc. |date=2007-10-04 |deadurl=no |access-date=26 November 2013}}</ref> In 2017, its development was abandoned by [[Merck & Co.|Merck]].<ref>{{cite news|title=Merck says will not seek approval of cholesterol treatment|url=https://www.reuters.com/article/us-merck-cholesterol/merck-says-will-not-seek-approval-of-cholesterol-treatment-idUSKBN1CG2W1|accessdate=18 October 2017|work=Reuters|date=2017}}</ref> The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.


A compound related to torcetrapib, going by the investigative name JTT-705/R1658, is undergoing studies.<ref>{{cite journal |author=El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ |year=2007 |month=Aug |title=The role of CETP inhibition in dyslipidemia |journal=Curr Atheroscler Rep |volume=9 |issue=2 |pages=125-33 |id=PMID 17877921}}</ref> It increases HDL levels by 30% (as compared to 60% by torcetrapib).<ref>{{cite journal |author=de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ |year=2002 |month=May |title=Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study |journal=Circulation |volume=105 |issue=18 |pages=2159-65 |id=PMID 11994249  |url=http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159}}</ref>. Another CETP inhibitor under development is Merck's MK-0859 [[anacetrapib]], which in initial studies has been shown not to increase blood pressure.<ref>{{cite news |author=Reuters|title=Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes | url=http://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004 |publisher=Reuters, Inc. |date=4 October 2007 |accessdate=2007-11-04}}</ref>
==Interactive pathway map==
{{StatinPathway_WP430|highlight=Cholesterylester_transfer_protein}}


==References==
== References ==
{{Reflist|2}}
{{Reflist|2}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{Refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Okajima F | title = [Distribution of sphingosine 1-phosphate in plasma lipoproteins and its role in the regulation of the vascular cell functions] | journal = Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme | volume = 47 | issue = 4 Suppl | pages = 480–7 | date = March 2002 | pmid = 11915346 }}
| citations =
* {{cite journal | vauthors = Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR | title = Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 2 | pages = 160–7 | date = February 2003 | pmid = 12588754 | doi = 10.1161/01.ATV.0000054658.91146.64 | url = http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=12588754 | format = Free full text }}
*{{cite journal | author=Okajima F |title=[Distribution of sphingosine 1-phosphate in plasma lipoproteins and its role in the regulation of the vascular cell functions] |journal=Tanpakushitsu Kakusan Koso |volume=47 |issue= 4 Suppl |pages= 480-7 |year= 2002 |pmid= 11915346 |doi=  }}
* {{cite journal | vauthors = Dallinga-Thie GM, Dullaart RP, van Tol A | title = Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins | journal = Current Opinion in Lipidology | volume = 18 | issue = 3 | pages = 251–7 | date = June 2007 | pmid = 17495597 | doi = 10.1097/MOL.0b013e3280e12685 }}
*{{cite journal | author=Barter PJ, Brewer HB, Chapman MJ, ''et al.'' |title=Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=23 |issue= 2 |pages= 160-7 |year= 2003 |pmid= 12588754 |doi= }}
{{Refend}}
*{{cite journal | author=Dallinga-Thie GM, Dullaart RP, van Tol A |title=Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins. |journal=Curr. Opin. Lipidol. |volume=18 |issue= 3 |pages= 251-7 |year= 2007 |pmid= 17495597 |doi= 10.1097/MOL.0b013e3280e12685 }}
}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Cholesterol+ester+transfer+proteins}}
* {{MeshName|Cholesterol+ester+transfer+proteins}}


{{PDB Gallery|geneid=1071}}
{{Glycoproteins}}
{{Glycoproteins}}
{{Carrier proteins}}
{{Carrier proteins}}
{{Lipoprotein metabolism}}


{{DEFAULTSORT:Cholesterylester Transfer Protein}}
[[Category:Blood proteins]]
[[Category:Blood proteins]]
[[Category:Cardiology]]
{{WH}}
{{WS}}

Latest revision as of 09:11, 10 January 2019

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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

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

Protein Fold

The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains.[1][2] Each domain consists of a core of 6 elements: 4 beta-sheets forming an extended superhelix; 2 flanking elements that tend to include some alpha helix. The sheets wrap around the helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets, 3 from each protomer. The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1 BPIFP2 BPIFA3 and BPIFB4), phospholipid transfer protein (PLTP), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC). The fold is similar to intracellular SMP domains,[3] and originated in bacteria.[4][5][6] The crystal structure of CETP has been obtained with bound CETP inhibitors.[7] However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.[8]

Role in disease

Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[9] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [10] and to metabolic response to nutritional intervention.[11] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[12] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[9]

Elaidic acid, a major component of trans fat, increases CETP activity.[13]

Pharmacology

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.[14] 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.[15] 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,[16][17] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[18]

A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased.[19] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[20] Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure.[21] In 2017, its development was abandoned by Merck.[22] The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.

Interactive pathway map

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

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Statin Pathway edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

References

  1. ↑ Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP (February 2007). "Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules". Nature Structural & Molecular Biology. 14 (2): 106–13. doi:10.1038/nsmb1197. PMID 17237796.
  2. ↑ Alva V, Lupas AN (August 2016). "The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport". Biochimica et Biophysica Acta. 1861 (8 Pt B): 913–923. doi:10.1016/j.bbalip.2016.01.016. PMID 26825693.
  3. ↑ Reinisch KM, De Camilli P (August 2016). "SMP-domain proteins at membrane contact sites: Structure and function". Biochimica et Biophysica Acta. 1861 (8 Pt B): 924–927. doi:10.1016/j.bbalip.2015.12.003. PMC 4902782. PMID 26686281.
  4. ↑ Wong LH, Levine TP (September 2017). "Tubular lipid binding proteins (TULIPs) growing everywhere". Biochimica et Biophysica Acta. 1864 (9): 1439–1449. doi:10.1016/j.bbamcr.2017.05.019. PMC 5507252. PMID 28554774.
  5. ↑ Lam KH, Qi R, Liu S, Kroh A, Yao G, Perry K, Rummel A, Jin R (June 2018). "The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein". Toxicon. 147: 19–26. doi:10.1016/j.toxicon.2017.10.012. PMC 5902665. PMID 29042313.
  6. ↑ Gustafsson R, Berntsson RP, Martínez-Carranza M, El Tekle G, Odegrip R, Johnson EA, Stenmark P (November 2017). "Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster". FEBS Letters. 591 (22): 3781–3792. doi:10.1002/1873-3468.12889. PMID 29067689.
  7. ↑ Liu S, Mistry A, Reynolds JM, Lloyd DB, Griffor MC, Perry DA, Ruggeri RB, Clark RW, Qiu X (October 2012). "Crystal structures of cholesteryl ester transfer protein in complex with inhibitors". The Journal of Biological Chemistry. 287 (44): 37321–9. doi:10.1074/jbc.M112.380063. PMC 3481329. PMID 22961980.
  8. ↑ Lauer ME, Graff-Meyer A, Rufer AC, Maugeais C, von der Mark E, Matile H, D'Arcy B, Magg C, Ringler P, Müller SA, Scherer S, Dernick G, Thoma R, Hennig M, Niesor EJ, Stahlberg H (May 2016). "Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP". Journal of Structural Biology. 194 (2): 191–8. doi:10.1016/j.jsb.2016.02.016. PMID 26876146.
  9. ↑ 9.0 9.1 Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR (June 1996). "Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels". The Journal of Clinical Investigation. 97 (12): 2917–23. doi:10.1172/JCI118751. PMC 507389. PMID 8675707.
  10. ↑ Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (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.
  11. ↑ Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A, Darabi M, Ghatrehsamani K (July 2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 41 (7): 554–8. doi:10.1055/s-0029-1192034. PMID 19242900.
  12. ↑ Bruce C, Sharp DS, Tall AR (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". Journal of Lipid Research. 39 (5): 1071–8. PMID 9610775.
  13. ↑ Abbey M, Nestel PJ (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.
  14. ↑ Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (2): 160–7. doi:10.1161/01.ATV.0000054658.91146.64. PMID 12588754.
  15. ↑ Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (April 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". The New England Journal of Medicine. 350 (15): 1505–15. doi:10.1056/NEJMoa031766. PMID 15071125.
  16. ↑ Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". The New England Journal of Medicine. 356 (13): 1304–16. doi:10.1056/NEJMoa070635. PMID 17387129.
  17. ↑ Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". The New England Journal of Medicine. 356 (16): 1620–30. doi:10.1056/NEJMoa071359. PMID 17387131.
  18. ↑ "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety" (Press release). U.S. Food and Drug Administration. 2006-12-03.
  19. ↑ El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (August 2007). "The role of CETP inhibition in dyslipidemia". Current Atherosclerosis Reports. 9 (2): 125–33. doi:10.1007/s11883-007-0008-5. PMID 17877921.
  20. ↑ de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ (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.
  21. ↑ 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.
  22. ↑ "Merck says will not seek approval of cholesterol treatment". Reuters. 2017. Retrieved 18 October 2017.

Further reading

External links

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