Add: s2cid. | Use this bot. Report bugs. | #UCB_CommandLine 88/13232
|
m →top: Confirm {{Use dmy dates}} from 2013; WP:GenFixes & cleanup on
|
||
(2 intermediate revisions by 2 users not shown) | |||
Line 1: | Line 1: | ||
⚫ | |||
{{Short description|Mammalian protein found in Homo sapiens}} |
{{Short description|Mammalian protein found in Homo sapiens}} |
||
⚫ | |||
{{Use dmy dates|date= |
{{Use dmy dates|date=May 2024}} |
||
{{Infobox_gene}} |
{{Infobox_gene}} |
||
'''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 [[Chylomicron]]s 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. |
'''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 [[Chylomicron]]s 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. |
||
Line 9: | Line 9: | ||
== Protein Fold == |
== 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 | s2cid = 30939809 }}</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 (BBA) - Molecular and Cell Biology of Lipids | 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]]), 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 (BBA) - Molecular and Cell Biology of Lipids | 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 (BBA) - Molecular Cell Research | 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 | doi-access = free }}</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 | doi-access = free }}</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 | doi-access = free }}</ref> |
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 | s2cid = 30939809 }}</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 (BBA) - Molecular and Cell Biology of Lipids | 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 (structural biology)|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]]), 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 (BBA) - Molecular and Cell Biology of Lipids | 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 (BBA) - Molecular Cell Research | 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 | doi-access = free }}</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 | doi-access = free }}</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 | doi-access = free }}</ref> |
||
==Role in disease== |
==Role in disease== |
||
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 | doi-access = }}</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 | volume = 41 | issue = 7 | pages = 554–8 | date = July 2009 | pmid = 19242900 | doi = 10.1055/s-0029-1192034 | s2cid = 260169359 }}</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 | doi = 10.1016/S0022-2275(20)33876-1 | pmid = 9610775 | doi-access = free }}</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 | doi-access = | s2cid = 22792639 }}</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 | volume = 41 | issue = 7 | pages = 554–8 | date = July 2009 | pmid = 19242900 | doi = 10.1055/s-0029-1192034 | s2cid = 260169359 }}</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 | doi = 10.1016/S0022-2275(20)33876-1 | pmid = 9610775 | doi-access = free }}</ref> The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.<ref name=Zhong1996/> |
||
[[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> |
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 Chylomicrons 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 chromosome 16 (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]
|alt=Statin pathway edit]] Statin pathway edit
| |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mucoproteins |
| ||||||||||
Proteoglycans |
| ||||||||||
Other |
|
| |
---|---|
Fatty acid |
|
Hormone |
|
Metal/element |
|
Vitamin |
|
Pigment |
|
Other |
|
Lipids: lipoprotein particle metabolism
| ||
---|---|---|
Lipoprotein particle classes and subclasses |
| |
Apolipoproteins |
| |
Extracellular enzymes |
| |
Lipid transfer proteins |
| |
Cell surface receptors |
| |
ATP-binding cassette transporter |
|