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==Role in disease== |
==Role in disease== |
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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- |
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/> |
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[[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> |
[[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> |
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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> |
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> |
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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 | |
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 |agency=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. |
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==Interactive pathway map== |
==Interactive pathway map== |
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.
The CETP gene is located on the sixteenth chromosome (16q21).
The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains.[3][4] 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,[5] and originated in bacteria.[6][7][8] The crystal structure of CETP has been obtained with bound CETP inhibitors.[9] However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.[10]
Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[11] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity[12] and to metabolic response to nutritional intervention.[13] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[14] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[11]
Elaidic acid, a major component of trans fat, increases CETP activity.[15]
AsHDL 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.[16] 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.[17] 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,[18][19] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[20]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased.[21] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[22] Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure.[23] In 2017, its development was abandoned by Merck.[24] The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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Lipid transfer proteins |
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ATP-binding cassette transporter |
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