Cholesteryl ester transfer protein
Lua error in Module:Infobox_gene at line 33: attempt to index field 'wikibase' (a nil value). 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.
Contents
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
<templatestyles src="Module:Hatnote/styles.css"></templatestyles>
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]
- ↑ The interactive pathway map can be edited at WikiPathways: Lua error in package.lua at line 80: module 'strict' not found.
References
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
Further reading
- Lua error in package.lua at line 80: module 'strict' not found.
- Lua error in package.lua at line 80: module 'strict' not found.
- Lua error in package.lua at line 80: module 'strict' not found.
External links
- Cholesterol ester transfer proteins at the US National Library of Medicine Medical Subject Headings (MeSH)