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]
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. [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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Aliases | CETP, BPIFF, HDLCQ10, cholesteryl ester transfer protein | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 118470 HomoloGene: 47904 GeneCards: CETP | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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 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]
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. [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]