Cholesterylester transfer protein

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 or low density lipoproteins (VLDL or LDL) and exchanges them for cholesteryl esters from high density lipoproteins (and vice versa). Most of the time, however, CETP does a homoexchange- trading a triglyceride for a triglyceride or a cholesteryl ester for a cholesteryl ester.

Genetics
The CETP gene is located on the sixteenth chromosome (16q21).

Role in disease
Rare mutations leading to increased function of CETP have been linked to accelerated atherosclerosis. In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity. However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.

Elaidic acid&mdash;a major component of trans fat&mdash;increases CETP activity.

Pharmacology
As HDL has a protective function in atherosclerosis and cardiovascular disease, and certain disease states (such as the metabolic syndrome) feature low HDL, pharmacological inhibition of CETP is being studied as a method to improve HDL levels. Specifically, 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) in a 2004 study. 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, and (in a trial of a combination of torcetrapib and atorvastatin) an increase in cardiovascular events and mortality.

A compound related to torcetrapib, going by the investigative name JTT-705/R1658, is undergoing studies. It increases HDL levels by 30% (as compared to 60% by torcetrapib). . Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies has been shown not to increase blood pressure.