cholesterol ester transfer protein
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Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that facilitates the transport of cholesteryl esters and
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...
s between the
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, su ...
s. It collects triglycerides from very-low-density (VLDL) or
Chylomicron Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...
s and exchanges them for cholesteryl esters from
high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
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.


Genetics

The ''CETP'' gene is located on the sixteenth
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
(16q21).


Protein Fold

The
crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns ...
of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains. 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 In structural biology, a protomer is the structural unit of an oligomeric protein. It is the smallest unit composed of at least two different protein chains that form a larger hetero-oligomer by association of two or more copies of this unit. The ...
. The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1 BPIFP2
BPIFA3 BPI fold containing family A, member 3 is a protein that in humans is encoded by the ''BPIFA3'' gene. The gene is also known as ''SPLUNC3 and C20orf71'' in humans and the orthologous gene in mice is ''1700058C13Rik''. Model organisms Model o ...
and
BPIFB4 BPI fold containing family B, member 4 is a protein that in humans is encoded by the BPIFB4 gene. The study of many populations of centenarians made it possible to identify the longevity-associated variant (LAV) of the BPIFB4 gene. The gene tra ...
), phospholipid transfer protein (
PLTP Phospholipid transfer protein is a protein that in humans is encoded by the ''PLTP'' gene. Function The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholip ...
), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC). The fold is similar to intracellular SMP domains, and originated in bacteria. The crystal structure of CETP has been obtained with bound
CETP inhibitors A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). They are intended to reduce the risk of atherosclerosis (a cardiovascular disease) by improving blood lipid levels. At least three medications ...
. However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.


Role in disease

Rare mutations leading to reduced function of CETP have been linked to accelerated
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
. In contrast, a polymorphism (I405V) of the ''CETP'' gene leading to lower serum levels has also been linked to exceptional longevity and to metabolic response to nutritional intervention. However, this mutation also increases the prevalence of
coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
in patients with
hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and ...
. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.
Elaidic acid Elaidic acid is a chemical compound with the formula , specifically the fatty acid with structural formula HO(O=)C–(CH2–)7CH=CH–(CH2–)8H, with the double bond (between carbon atoms 9 and 10) in ''trans'' configuration. It is a colorle ...
, a major component of
trans fat Trans fat, also called trans-unsaturated fatty acids, or trans fatty acids, is a type of unsaturated fat that naturally occurs in small amounts in meat and milk fat. It became widely produced as an unintentional byproduct in the industrial pr ...
, increases CETP activity.


Pharmacology

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. To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...
, and lower LDL when co-administered with a statin. Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
levels, most reported an increase in blood pressure, no change in atherosclerosis, and, in a trial of a combination of torcetrapib and
atorvastatin Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth. Common ...
, an increase in cardiovascular events and mortality. A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased. It increases HDL levels by 30%, as compared to 60% by torcetrapib. Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure. In 2017, its development was abandoned by Merck. The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.


Interactive pathway map


References


Further reading

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External links

* {{DEFAULTSORT:Cholesterylester Transfer Protein Blood proteins