Cholesterol ester transfer protein

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Cholesterol ester transfer protein
Cholesterol ester transfer protein
Belt model from CETP seen from two sides, according to PDB  2OBD
Properties of human protein
Mass / length primary structure 476 amino acids
Isoforms 2
Identifier
Gene name CETP
External IDs
Transporter classification
TCDB 1.C.40.1.4
designation BPIP family
Occurrence
Homology family BPI / LBP
Parent taxon Vertebrates

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

From a biochemical point of view, CETP is a pore-forming protein. In humans, it is primarily formed in the liver and from there released into the blood . It circulates in the blood mainly bound to high density lipoproteins ( HDL ). Mutations in the CETP - gene are the cause of a rare hereditary disease with elevated HDL levels.

Mechanism of action of CETP

CETP is a transfer protein that absorbs neutral fats ( e.g. triglycerides and cholesterol esters ) from a donor particle in its hydrophobic tunnel, transports it through the aqueous phase and releases it to lipoprotein acceptors.

CETP is of central importance for the lipoprotein metabolism in the human organism. On the one hand, CETP mediates the transfer of cholesterol esters from HDL to Low Density Lipoproteins (LDL) or Very Low Density Lipoproteins (VLDL). These transport the cholesterol primarily to the periphery. This activity of CETP, which tends to have a pro-atherogenic effect, is called heterotypic activity. On the other hand, CETP is also significantly involved in lipid transfer within the HDL fractions, the maturation process of the HDL particles (HDL remodeling). Since HDL transports cholesterol from the blood vessels back to the liver cells as part of the reverse cholesterol transport, which ultimately excrete the cholesterol in the form of bile acid and free cholesterol via the bile, this so-called homotypic activity of CETP has an antiatherogenic effect.

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 from the anti-atherogenic HDL to the pro-atherogenic LDL. Therefore, CETP activity tends to promote atherosclerosis. From an evolutionary perspective, CETP is likely to have evolved as a tool with which vital cholesterol is retained in the body. Given the changed nutritional conditions of the present, the pro-atherogenic effect is now in the foreground.

CETP inhibition and modulation

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

An inhibition or modulation of CETP activity causes, among other things:

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

CETP inhibition or modulation have an anti-atherogenic potential, particularly due to their effects on the HDL fraction with an increase in the HDL particle number and HDL concentration. Elevated HDL cholesterol levels in the blood were associated with a lower cardiovascular event rate in the Framingham study and in the TNT study, among others. 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 led to an inhibition of atherosclerosis. For these reasons, among others, CETP inhibition and modulation are seen as promising approaches for the treatment of dyslipidemia or as possible treatment options for reducing the increased cardiovascular risk associated with a lipid metabolism disorder.

CETP inhibitors and modulators

CETP inhibitors and modulators are pharmacological substances that cause 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 the mechanism of action.

In clinical development were or are among other CETP inhibitors torcetrapib , anacetrapib and Evacetrapib and the CETP modulator Dalcetrapib . In contrast to the first three substances, which completely block CETP by forming a triple complex of HDL, CETP and active ingredient, dalcetrapib merely inhibits lipid transfer between HDL and LDL / VLDL. While the older CETP inhibitor torcetrapib could not meet expectations, newer substances such as anacetrapib and dalcetrapib showed in clinical studies not only a favorable influence on the lipoprotein profile but also a favorable side effect profile. Due to the complex interrelationships of the CETP effect, the increase in HDL cholesterol alone is not a sufficient marker for clinical benefit. A central parameter seems to be the functionality of the HDL particles themselves. An essential function of HDL in the context of reverse cholesterol transport is the uptake of cholesterol from the macrophages (cholesterol efflux). Study data show that a high cholesterol efflux capacity is associated with a lower risk of coronary heart disease regardless of the level of HDL cholesterol. Ultimately, however, the decisive factor with regard to a possible therapeutic benefit is whether the substances can demonstrate a reduction in the cardiovascular event rate in clinical studies.

Torcetrapib

The manufacturer Pfizer stopped developing torcetrapib back in 2006. 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 study ILLUMINATE in patients with cardiovascular diseases. There was a statistically significant increase in HDL cholesterol levels of 72 percent. Nevertheless, the study was discontinued because treatment with torcetrapib was associated with an increased risk of cardiovascular events and increased mortality. An increase in blood pressure of 5.4 mmHg under torcetrapib is discussed as a possible cause of the increased mortality . The 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 the complex formation mentioned, which could have had adverse effects on the function of the protective HDL particles. At the same time, however, a subsequent analysis of the ILLUMINATE study also shows an improvement in glycemic control in type 2 diabetics taking torcetrapib. Treatment with the CETP inhibitor in this subgroup led, among other things, to a lowering of the blood sugar level and the HbA 1c value. These events indicate the protective potential of higher HDL concentrations on the beta cell.

Anacetrapib

The CETP inhibitor anacetrapib from MSD is currently being tested in a clinical phase III study - first results are not expected before 2016. In a phase III safety study in patients with dyslipidemia, the HDL-C concentration rose by 139 percent, while the LDL-C concentration fell by almost 40 percent. The actual clinical effects of these altered parameters, as well as the precise mechanism of action of anacetrapib, are the subject of further investigation. There was no evidence of an increase in blood pressure during therapy with anacetrapib. One problem with anacetrapib appears to be that after ingestion it stays in the body for up to 4 years without being completely eliminated.

Evacetrapib

The CETP inhibitor evacetrapib from Lilly is also in clinical phase III.

Dalcetrapib

A CETP modulator was tested in clinical studies with dalcetrapib from Roche . The clinical development of this substance was also stopped in 2012. 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 completely inhibit CETP activity. Instead, it induces a change in the CETP conformation, whereby the heterotypic activity of CETP, the mediation of cholesterol transfer from HDL to LDL and VLDL, is suppressed. The homotypic activity, i.e. H. the lipid transfer within the HDL fractions (HDL remodeling), on the other hand, is not influenced. This suggests that the functionality of the HDL particle is fully retained under dalcetrapib. Animal experiments on hamsters also show that therapy with dalcetrapib increased the excretion of cholesterol breakdown products, i.e. the reverse cholesterol transport was increased. This also indicates that HDL will continue to function.

In phase II clinical studies, dalcetrapib increased HDL cholesterol by approximately 30 percent. There was neither an increase in blood pressure nor an induction of aldosterone synthase. In phase IIb studies, dalcetrapib also showed a side effect profile that was comparable to treatment with placebo. As a consequence of the favorable phase II data, dalcetrapib was investigated in the comprehensive dal-HEART study program. It comprised 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 ) in 2011, confirmed the beneficial influence of dalcetrapib on the lipid profile. The studies also confirmed the good tolerability and safety of dalcetrapib: the endothelial function was not negatively affected; the blood pressure did not rise. In addition, dalcetrapib caused a significant reduction in the total vessel area, which indicates a weakened progression of atherosclerosis compared to placebo. However, the Phase III studies with 15,000 subjects were terminated by Roche in early May 2012 due to a lack of clinical efficacy.

Individual evidence

  1. ↑ a b c d e f g Tall AR: Plasma cholesteryl ester transfer protein . (PDF): J. Lipid Res. . 34, No. 8, August 1993, pp. 1255-74. PMID 8409761 .
  2. ↑ a b c d e f g h i Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR: Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis . In: Arterioscler. Thromb. Vasc. Biol . 23, No. 2, February 2003, pp. 160-7. PMID 12588754 .
  3. ↑ a b Barter PJ, Hopkins GJ, Calvert GD: Transfers and exchanges of esterified cholesterol between plasma lipoproteins . In: Biochem. J. . 208, No. 1, October 1982, pp. 1-7. PMID 6760853 . PMC 1153921 (free full text).
  4. ↑ a b von Eckardstein A, Nofer JR, Assmann G: High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport . In: Arterioscler. Thromb. Vasc. Biol . 21, No. 1, January 2001, pp. 13-27. PMID 11145929 .  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Dead Link / atvb.ahajournals.org  
  5. ↑ a b c d Niesor EJ: Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism . In: Current Opinion in Lipidology . 22, 2011, pp. 288-295.
  6. ↑ a b c d e Cannon CP et al .: Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease . In: NEJM . 363, 2010, pp. 2406-2415.
  7. ↑ Matsuura F, Wang N, Chen W, Jiang XC, Tall AR: HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway . In: J. Clin. Invest. . 116, No. 5, May 2006, pp. 1435-42. doi : 10.1172 / JCI27602 . PMID 16670775 . PMC 1451209 (free full text).
  8. ↑ Kontush, Chapman: Pharmacol Rev . 2006; No. 58: pp. 342-374.
  9. ^ Castelli et al .: Can J Cardiol. 1988; No. 4 (suppl. A): pp. 5A-10A.
  10. ↑ Barter PJ, Caulfield M, Eriksson M, et al. : Effects of torcetrapib in patients at high risk for coronary events . In: N. Engl. J. Med. . 357, No. 21, November 2007, pp. 2109-22. doi : 10.1056 / NEJMoa0706628 . PMID 17984165 .
  11. ↑ a b Stein EA, Stroes ES, Steiner G, et al. : Safety and tolerability of dalcetrapib . In: Am. J. Cardiol. . 104, No. 1, July 2009, pp. 82-91. doi : 10.1016 / j.amjcard.2009.02.061 . PMID 19576325 .
  12. ↑ a b Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG: Safety and tolerability of dalcetrapib (RO4607381 / JTT-705): results from a 48-week trial . In: Eur Heart J. . 31, No. 4, February 2010, pp. 480-8. doi : 10.1093 / eurheartj / ehp601 . PMID 20097702 . PMC 2821630 (free full text).
  13. ↑ Khera AV et al .: Cholesterol Efflux Capacity, High Density Lipoprotein Function, and Atherosclerosis . In: N. Engl. J. Med. . 364, 2011, pp. 127-135.
  14. ↑ a b Stop for Dalcetrapib / Torcetrapib , Deutsche Apotheker Zeitung of May 15, 2012, accessed on July 27, 2015
  15. ↑ Niesor et al .: Atherosclerosis. 2008; No. 199: p. 231.
  16. ^ A b Clark RW, Ruggeri RB, Cunningham D, Bamberger MJ: Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action . In: J. Lipid Res . 47, No. 3, March 2006, pp. 537-52. doi : 10.1194 / jlr.M500349-JLR200 . PMID 16326978 .
  17. ↑ Barter P et al., Circulation 2011; 124: 555-562: Effect of Torcetrapib on Glucose, Insulin and Hemoglobin A 1c in Subjects in the Investigation of Lipid Level Management to Understand its Impact in Athereosclerotic Events (ILLUMINATE) Trial.
  18. ↑ a b Home - ClinicalTrials.gov .
  19. ↑ Bloomfield et al .: Am Heart J . 2009; No. 157: pp. 352-360
  20. ↑ Doctors newspaper online, November 19, 2010: HDL cholesterol increased dramatically with a new drug
  21. ↑ Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Patients With or at High Risk for Coronary Heart Disease , The American Journal of Cardiology, Volume 113, Issue 1, January 1, 2014 , Pages 76-83
  22. ↑ Lilly Provides Update on Evacetrapib Phase 3 Trial  ( page can no longer be accessed , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. , PM Lilly, July 27, 2015, accessed July 28, 2015.@1@ 2Template: Dead Link / investor.lilly.com  
  23. ^ AHA, Scientific Sessions, Orlando, Nov. 16, 2009, Poster 1092.
  24. ^ AHA, Scientific Sessions, Orlando, Nov. 17, 2009, Presentation 1271.
  25. ↑ Lüscher TF et al., ESC Congress 2011: dal-VESSEL: Efficacy and safety of dalcetrapib in patients with or at risk of coronary heart disease - the dal-VESSEL trial ( Memento of the original from May 21, 2013 in the Internet Archive ) Info : The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.escardio.org
  26. ↑ Fayad ZA et al .: Safety and efficacy on atherosclerotic diseaese using novel non-invasive multimodality imaging (dal-PLAQUE): a randomized clinical trial . In: The Lancet . September 2011.
  27. ↑ Press release from Roche GmbH dated May 7, 2012: Roche informs about the phase III study with dalcetrapib (PDF; 81 kB)
  28. ↑ FOCUS Online: Company: Roche stops phase III study for cardiovascular drug Dalcetrapib