Cholesterylester transfer protein

Cholesterol ester transfer protein ( CETP) is one of several proteins that are involved in vertebrates cholesterol transport between various lipoprotein fractions.

Biochemically CETP is a pore-forming protein. In humans it is produced primarily in the liver and released into the blood from there. In the blood, it circulates mainly bound to high-density lipoproteins ( HDL). Mutations in the CETP gene are the cause of a rare inherited disorder with elevated HDL-C levels.

Mechanism of action of CETP

CETP is a transfer protein, neutral fats (e.g., triglycerides and cholesterol ester ) receives from a Donorpartikel in its hydrophobic tunnel, transport through the aqueous phase, and delivers it to lipoprotein acceptors.

For lipoprotein metabolism in the human organism CETP is of central importance. On the one hand provides the CETP cholesterol ester transfer from HDL to low density lipoproteins (LDL) or very low density lipoproteins ( VLDL). This transport cholesterol mainly in the periphery. This activity of CETP, the pro- atherogenic effect tends to be referred to as a heterotypic activity. On the other hand, the CETP is also instrumental in the lipid transfer involved in the HDL fractions, the maturation process of HDL particles ( HDL remodeling). Since HDL transports cholesterol in the context of reverse cholesterol transport from the vessels back to the liver cells, which eventually excrete the cholesterol in the form of bile acid and free cholesterol in the bile, acts this so-called homotypic activity of CETP antiatherogenic.

CETP and atherosclerosis

The interaction between CETP activity and the development of atherosclerotic vascular changes is complex. The main function of CETP in the human organism is the transport of cholesterol to HDL anti- atherogenic in the direction of pro-atherogenic LDL. Therefore, CETP activity affects tend promoting atherosclerosis. From a evolutionary perspective, CETP may have developed as a tool that is retained with the necessary life- cholesterol in the body. Among the changes in dietary conditions of the present is now the pro- atherogenic effect in the foreground.

CETP inhibition and modulation

CETP activity can be pharmacologically affected. A distinction is made between CETP inhibitors that both the heterotypic and homotypic affect the activity, and CETP modulators that selectively heterotypic activity, the pro-atherogenic transfer between HDL and LDL / VLDL inhibit.

Inhibition or modulation of CETP activity causes, among other things:

  • Increasing the HDL Concentration
  • Increasing the concentration of apolipoprotein A1 and the ApoA -1 levels
  • Increase the total number of HDL particles
  • Increasing the HDL particle size
  • Reduction of the LDL level
  • Increase LDL particle size
  • Reduction of the cholesterol content of chylomicrons and VLDL

Especially through their effects on the HDL fraction with increase of HDL, and HDL particle number concentration, the CETP inhibition or modulation have an anti- atherogenic potential. Increased HDL - cholesterol levels in the blood have included in the Framingham study and in the TNT study associated with a lower cardiovascular event rate. It is also known that a CETP deficiency in humans is associated with a significant increase in HDL cholesterol. Finally, the inhibition of CETP activity in animal models consistently resulted in an inhibition of atherosclerosis. Partly for these reasons, the CETP inhibition and modulation are considered as promising approaches to the treatment of dyslipidemia or as a potential treatment options to reduce the fat with a metabolic disorder associated increased cardiovascular risk.

CETP inhibitors and modulators

CETP inhibitors and modulators are pharmacological substances which effect a complete or selective inhibition of CETP activity. This is a heterogeneous class of substances whose representatives differ in terms of chemical structure, physicochemical properties and mechanism of action.

In clinical development were or are, among others, the CETP inhibitors torcetrapib and anacetrapib and the CETP modulator dalcetrapib. In contrast to torcetrapib and anacetrapib, which completely by the formation of a triple complex of HDL, CETP and drug block the CETP, dalcetrapib only causes an inhibition of lipid transfer between HDL and LDL / VLDL. During the CETP inhibitor torcetrapib older could not meet the expectations, showed newer agents such as anacetrapib and dalcetrapib in clinical trials in addition to a favorable effect on the lipoprotein profile and a favorable side -effect profile. Due to the complex interrelationships of the CETP effect the increase of HDL cholesterol by itself is not a sufficient marker for clinical benefit. A key parameter appears to be even the functionality of HDL particles. A primary function of HDL in the context of reverse cholesterol transport is the absorption of cholesterol from the macrophages (cholesterol efflux ). Evidence shows data that a high cholesterol efflux capacity goes hand in hand regardless of the level of HDL - cholesterol levels with a lower risk of coronary heart disease. Crucial in terms of a possible therapeutic benefit is ultimately, however, whether the substances are able to demonstrate a reduction in cardiovascular event rates in clinical trials.

Torcetrapib

The binding of torcetrapib to CETP leads to the formation of a high-affinity complex of torcetrapib, CETP and HDL. The effect of the substance on the cardiovascular event rate was investigated in the phase III trial ILLUMINATE in patients with cardiovascular disease. There was a statistically significant increase in HDL - cholesterol levels by 72 percent. Nevertheless, the study was terminated because the treatment with torcetrapib was associated with an increased risk of cardiovascular events and increased mortality associated. A possible cause for the increased mortality is discussed, among other things, an increase in blood pressure of 5.4 mmHg under torcetrapib. Cause of this effect could have been an induction of the expression of aldosterone synthase. Another explanation is the specific mechanism of action of torcetrapib with said complex formation that could have had adverse effects on the function of the protective HDL particles. At the same time, however, a post-hoc analysis of the ILLUMINATE study shows an improvement of glycemic control in type 2 diabetic patients with torcetrapib. Thus, treatment with the CETP inhibitor in this subgroup among other things, a decrease in blood glucose and HbA1c. These events indicate the protective potential of higher HDL concentrations on the beta cell.

Anacetrapib

The CETP inhibitor anacetrapib is currently being tested in a clinical phase III trial - first results will not be before 2016 erwartet.In a Phase III safety study in patients with dyslipidemia showed an increase in HDL - C concentration by 139 percent, the LDL - C concentration decreased simultaneously by almost 40 percent. The actual clinical impact of these changes in parameters, as well as the exact mechanism of action of anacetrapib, the subject of further investigations. Evidence of an increase in blood pressure during treatment with anacetrapib did not exist.

Dalcetrapib

With the manufacturer Roche dalcetrapib a CETP modulator has been tested in clinical trials. Dalcetrapib binds exclusively to CETP and does not lead to the formation of triple complexes with HDL. In contrast to the CETP inhibitors Dalcetrapib does not cause complete inhibition of CETP activity. Instead, it induces a change in the conformation of CETP so that the heterotypic activity of CETP, the HDL mediation of Cholsterintransfers of LDL and VLDL, is suppressed. The homotypic activity, that is, the lipid transfer within the HDL fractions (HDL remodeling ) will not be affected. This suggests that the functionality of HDL particles undter dalcetrapib is fully maintained. Animal experiments on hamsters also show that in the treatment with dalcetrapib the excretion of cholesterol degradation products increased, the reverse cholesterol transport was thus strengthened. This also suggests that HDL is retained in its function.

In clinical phase II studies dalcetrapib induced an increase in HDL cholesterol by about 30 percent. There was neither an increase in blood pressure or to an induction of aldosterone. In Phase IIb trials also showed a dalcetrapib in the treatment of side-effect profile similar to placebo. As a consequence of the favorable phase II data dalcetrapib was examined in the comprehensive study program dal -HEART. It included five Phase III studies in patients with coronary heart disease. First results from the two studies dal - VESSEL and dal - PLAQUE, which were presented at the Annual Meeting of the European Society of Cardiology (ESC ) 2011, confirmed the beneficial effect of dalcetrapib on the lipid profile. The studies also demonstrated once again the good tolerability and safety of dalcetrapib: Endothelial function was not adversely affected; the blood pressure did not increase. In addition, dalcetrapib caused a significant reduction in the total vessel surface (Total Vessel Area), indicating an attenuated compared to placebo progression of atherosclerosis. However, phase III trials have been completed with 15,000 subjects due to lack of clinical efficacy in early May 2012 by Roche.

Protein isoform Human Genome Organisation Blood plasma Cholesteryl ester Biochemical Journal PubMed Central Digital Object Identifier The Lancet
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