Cholesteryl ester transfer protein

Genetics

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

Protein fold

The crystal structure of CETP is that of dimer of two tubular lipid (TULIP) binding domains. Each domain consists of a core of six elements: four beta-sheets forming an extended superhelix and two flanking elements that tend to include some alpha helices. 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 six beta-sheets, three from each protomer. The same fold is shared by bacterial permeability inducing proteins (such as 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, and originated in bacteria. The crystal structure of CETP has been obtained with bound CETP inhibitors. 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. 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 in patients with hypertriglyceridemia. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.

Elaidic acid, a common type of trans fat, 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, and lower LDL when co-administered with a statin. 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, 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

References

1. (February 2007). "Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules". Nature Structural & Molecular Biology.
2. (August 2016). "The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
3. (August 2016). "SMP-domain proteins at membrane contact sites: Structure and function". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
4. (September 2017). "Tubular lipid binding proteins (TULIPs) growing everywhere". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.
5. (June 2018). "The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein". Toxicon.
6. (November 2017). "Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster". FEBS Letters.
7. (October 2012). "Crystal structures of cholesteryl ester transfer protein in complex with inhibitors". The Journal of Biological Chemistry.
8. (May 2016). "Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP". Journal of Structural Biology.
9. (June 1996). "Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels". The Journal of Clinical Investigation.
10. (October 2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA.
11. (July 2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Hormone and Metabolic Research.
12. (May 1998). "Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia". Journal of Lipid Research.
13. (March 1994). "Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet". Atherosclerosis.
14. (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology.
15. (April 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". The New England Journal of Medicine.
16. (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". The New England Journal of Medicine.
17. (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". The New England Journal of Medicine.
18. (2006-12-03). "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety". U.S. Food and Drug Administration.
19. (August 2007). "The role of CETP inhibition in dyslipidemia". Current Atherosclerosis Reports.
20. (May 2002). "Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study". Circulation.
21. (2007-10-04). "Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes". Reuters, Inc..
22. (2017). "Merck says will not seek approval of cholesterol treatment". Reuters.