Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasmaprotein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (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.
The CETP gene is located on the sixteenth chromosome (16q21).
Role in disease
Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[1] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [2] and to metabolic response to nutritional intervention.[3] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[4] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[1]
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.[6] 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.[7] 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,[8][9] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[10]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also being studied, but trials have since been ceased.[11] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[12] Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies is not shown to increase blood pressure.[13]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
^Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A et al. (2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Horm Metab Res41 (7): 554–8. doi:10.1055/s-0029-1192034. PMID19242900.
^Abbey M, Nestel PJ (March 1994). "Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet". Atherosclerosis106 (1): 99–107. doi:10.1016/0021-9150(94)90086-8. PMID8018112.
^Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arterioscler Thromb Vasc Biol23 (2): 160–7. doi:10.1161/01.ATV.0000054658.91146.64. PMID12588754.
^Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT et al. (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med356 (13): 1304–16. doi:10.1056/NEJMoa070635. ISSN0028-4793. PMID17387129.
^Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ et al. (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". N Engl J Med356 (16): 1620–30. doi:10.1056/NEJMoa071359. PMID17387131.
^El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (August 2007). "The role of CETP inhibition in dyslipidemia". Curr Atheroscler Rep9 (2): 125–33. doi:10.1007/s11883-007-0008-5. PMID17877921.
Okajima F (March 2002). "[Distribution of sphingosine 1-phosphate in plasma lipoproteins and its role in the regulation of the vascular cell functions]". Tanpakushitsu Kakusan Koso47 (4 Suppl): 480–7. ISSN0039-9450. PMID11915346.
Dallinga-Thie GM, Dullaart RP, van Tol A (June 2007). "Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins". Curr. Opin. Lipidol.18 (3): 251–7. doi:10.1097/MOL.0b013e3280e12685. ISSN0957-9672. PMID17495597.