Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk
2012; Elsevier BV; Volume: 53; Issue: 9 Linguagem: Inglês
10.1194/jlr.r024075
ISSN1539-7262
AutoresPhilip J. Barter, Kerry-Anne Rye,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoHuman and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib. Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib. acute coronary syndrome cholesteryl ester transfer protein coronary heart disease cardiovascular endothelin-1 endothelial nitric oxide synthase HDL cholesterol homeostasis model assessment of insulin resistance LDL cholesterol triglyceride triglyceride-rich lipoprotein Population studies have identified the concentration of low-density lipoprotein (LDL) cholesterol as a positive predictor of having an atherosclerotic cardiovascular (CV) event (1Di Angelantonio E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. Packard C.J. et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1965) Google Scholar). Furthermore, intervention studies have shown that reducing the concentration of LDL cholesterol (LDL-C) by treatment with statins decreases the risk of having a CV event (2Baigent C. Blackwell L. Emberson J. Holland L.E. Reith C. Bhala N. Peto R. Barnes E.H. Keech A. Simes J. et al.Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (4534) Google Scholar). However, even aggressive statin therapy does not eliminate CV risk. One factor that may contribute to residual CV risk in statin-treated patients is a low level of high-density lipoprotein (HDL) cholesterol. Prospective population studies have also identified a low level of HDL cholesterol (HDL-C) as an independent predictor of CV risk (1Di Angelantonio E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. Packard C.J. et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1965) Google Scholar). This relationship persists even when LDL-C has been decreased to very low levels by treatment with statins (3Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1295) Google Scholar). Furthermore, as outlined below, HDLs have several properties with the potential to protect against the development of atherosclerosis (4Rye K.A. Bursill C.A. Lambert G. Tabet F. Barter P.J. The metabolism and anti-atherogenic properties of HDL.J. Lipid Res. 2009; 50 (Suppl.): S195-S200Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). Although there is still no direct evidence from clinical outcome trials in humans that raising the level of HDL-C will translate into a reduction in clinical CV events, there is a large and compelling body of evidence in animal studies (5Badimon J.J. Badimon L. Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.J. Clin. Invest. 1990; 85: 1234-1241Crossref PubMed Scopus (674) Google Scholar–8Plump A.S. Scott C.J. Breslow J.L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse.Proc. Natl. Acad. Sci. USA. 1994; 91: 9607-9611Crossref PubMed Scopus (546) Google Scholar) and growing evidence in human studies (9Nissen S.E. Tsunoda T. Tuzcu E.M. Schoenhagen P. Cooper C.J. Yasin M. Eaton G.M. Lauer M.A. Sheldon W.S. 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These observations have collectively led to a major research effort to identify therapies with the capacity to raise the concentration of HDL-C as effectively as statins reduce LDL-C levels. One logical therapeutic approach to raising the concentration of HDL-C is to shift the partitioning of cholesterol between LDLs and HDLs in favor of the protective HDL fraction. Given that i) most of the cholesterol in human plasma exists in the form of cholesteryl esters, ii) most of the cholesteryl esters in human plasma originate in HDLs where they are formed in the reaction catalyzed by lecithin:cholesterol acyltransferase (LCAT), and iii) human plasma contains a cholesteryl ester transfer protein (CETP) that promotes the transfer of cholesteryl esters from HDLs to other lipoprotein particles (including LDLs) (11Barter P.J. Jones M.E. Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins.J. Lipid Res. 1980; 21: 238-249Abstract Full Text PDF PubMed Google Scholar–14Ha Y.C. Barter P.J. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species.Comp. Biochem. Physiol. B. 1982; 71: 265-269Crossref PubMed Scopus (46) Google Scholar), it follows that inhibition of CETP has the potential to retain cholesterol in the HDL fraction and thus increase the concentration of HDL-C while decreasing its concentration in potentially atherogenic, non-HDL particles. CETP is a hydrophobic glycoprotein (15Hesler C.B. Swenson T.L. Tall A.R. Purification and characterization of a human plasma cholesteryl ester transfer protein.J. Biol. Chem. 1987; 262: 2275-2282Abstract Full Text PDF PubMed Google Scholar) that is synthesized in several tissues but mainly in the liver (16Drayna D. Jarnagin A.S. McLean J. Henzel W. Kohr W. Fielding C. Lawn R. Cloning and sequencing of human cholesteryl ester transfer protein cDNA.Nature. 1987; 327: 632-634Crossref PubMed Scopus (301) Google Scholar). Its crystal structure has been reported and reveals a curved molecule with N- and C-terminal cavities that provide access to cholesteryl esters and triglycerides and a tunnel spanning the entire length of the protein (17Qiu X. Mistry A. Ammirati M.J. Chrunyk B.A. Clark R.W. Cong Y. Culp J.S. Danley D.E. Freeman T.B. Geoghegan K.F. et al.Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.Nat. Struct. Mol. Biol. 2007; 14: 106-113Crossref PubMed Scopus (213) Google Scholar). CETP promotes bidirectional transfers of cholesteryl esters and triglyceride between all plasma lipoprotein particles (12Barter P.J. Hopkins G.J. Calvert G.D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins.Biochem. J. 1982; 208: 1-7Crossref PubMed Scopus (146) Google Scholar). Two hypotheses have been proposed for the mechanism by which CETP transfers neutral lipids between plasma lipoproteins: i) a shuttle mechanism that involves CETP collecting cholesteryl esters from one lipoprotein and delivering them through the aqueous phase to another lipoprotein (Fig. 1) (12Barter P.J. Hopkins G.J. Calvert G.D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins.Biochem. J. 1982; 208: 1-7Crossref PubMed Scopus (146) Google Scholar, 18Swenson T.L. Brocia R.W. Tall A.R. Plasma cholesteryl ester transfer protein has binding sites for neutral lipids and phospholipids.J. Biol. Chem. 1988; 263: 5150-5157Abstract Full Text PDF PubMed Google Scholar, 19Tall A.R. Plasma cholesteryl ester transfer protein.J. Lipid Res. 1993; 34: 1255-1274Abstract Full Text PDF PubMed Google Scholar), and ii) a tunnel mechanism in which CETP bridges two lipoproteins to form a ternary complex, with lipids flowing from the donor to acceptor lipoprotein through the CETP molecule (Fig. 2) (20Ihm J. Quinn D.M. Busch S.J. Chataing B. Harmony J.A. Kinetics of plasma protein-catalyzed exchange of phosphatidylcholine and cholesteryl ester between plasma lipoproteins.J. Lipid Res. 1982; 23: 1328-1341Abstract Full Text PDF PubMed Google Scholar–22Zhang L. Yan F. Zhang S. Lei D. Charles M.A. Cavigiolio G. Oda M. Krauss R.M. Weisgraber K.H. Rye K.A. et al.Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein.Nat. Chem. Biol. 2012; 8: 342-349Crossref PubMed Scopus (107) Google Scholar).Fig. 2Proposed tunnel mechanism for cholesteryl ester transfer by CETP. The N-terminal of CETP initially penetrates the HDL surface and forms a binary complex in which the CETP interacts with the cholesteryl ester core of HDL. The binary complex then interacts with LDL or VLDL via the C-terminal domain of CETP to form a ternary complex consisting of HDL, CETP, and VLDL/LDL. Molecular forces introduced by the lipoproteins at either end of the CETP molecule cause twisting of the CETP molecule that results in the formation of a tunnel through which cholesteryl esters are transferred from HDL to LDL or VLDL. The ternary complex then dissociates to form VLDL/LDL particles that are enriched in cholesteryl esters and HDL particles that are depleted of cholesteryl esters and reduced in size.View Large Image Figure ViewerDownload Hi-res image Download (PPT) As shown schematically in Fig. 1, CETP collides randomly with particles in all lipoprotein fractions to form transient lipoprotein-CETP complexes that facilitate exchanges of both cholesteryl esters and triglycerides between lipoprotein particles and CETP. The CETP, along with its associated neutral lipids, subsequently dissociates from the lipoprotein particles and circulates in a free state until it collides with another lipoprotein particle in either the same (23Barter P.J. Ha Y.C. Calvert G.D. Studies of esterified cholesterol in sub-fractions of plasma high density lipoproteins.Atherosclerosis. 1981; 38: 165-175Abstract Full Text PDF PubMed Scopus (40) Google Scholar) or in a different (12Barter P.J. Hopkins G.J. Calvert G.D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins.Biochem. J. 1982; 208: 1-7Crossref PubMed Scopus (146) Google Scholar) lipoprotein fraction to form a new transient complex that facilitates further exchange of cholesteryl esters and triglyceride between the lipoprotein particle and CETP. In this way, CETP promotes an equilibration of both cholesteryl esters and triglycerides among all lipoprotein particles. Because most of the cholesteryl esters in plasma are generated in HDLs by the LCAT reaction and although the majority of the triglyceride enters plasma as a component of chylomicrons and VLDLs [known collectively as triglyceride-rich lipoproteins (TRL)], the net effect of the neutral lipid equilibration promoted by CETP is a mass transfer of cholesteryl esters from the HDL fraction to the LDL-TRL fraction and of triglyceride from TRLs to HDLs (Fig. 3). Under normal physiological conditions, the rate of CETP-mediated cholesteryl ester transfer is rapid relative to the rate of catabolism of HDLs and LDLs (11Barter P.J. Jones M.E. Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins.J. Lipid Res. 1980; 21: 238-249Abstract Full Text PDF PubMed Google Scholar, 12Barter P.J. Hopkins G.J. Calvert G.D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins.Biochem. J. 1982; 208: 1-7Crossref PubMed Scopus (146) Google Scholar), such that the pools of cholesteryl esters in HDLs and LDLs are close to complete equilibrium in vivo. This view is supported by the observation that when HDLs and LDLs are incubated in vitro in the presence of CETP, there is a high rate of bidirectional transfer of radiolabeled cholesteryl esters but no net mass transfer in either direction (11Barter P.J. Jones M.E. Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins.J. Lipid Res. 1980; 21: 238-249Abstract Full Text PDF PubMed Google Scholar). As a consequence of the pools of cholesteryl esters in HDLs and LDLs already being close to equilibrium in vivo, any increase in the activity of CETP beyond physiological levels would be predicted to have little impact on the distribution of cholesteryl esters between these lipoprotein fractions. In contrast, if the activity of CETP was inhibited, a point will be reached where CETP activity becomes rate limiting and will affect the distribution of cholesteryl esters between LDLs and HDLs in vivo. The tunnel mechanism involves the initial formation of a binary complex between an HDL particle and a CETP molecule, with the subsequent formation (following a collision between the binary complex and an LDL or VLDL particle) of a ternary complex consisting of two lipoprotein particles bridged by a molecule of CETP (Fig. 2) (20Ihm J. Quinn D.M. Busch S.J. Chataing B. Harmony J.A. Kinetics of plasma protein-catalyzed exchange of phosphatidylcholine and cholesteryl ester between plasma lipoproteins.J. Lipid Res. 1982; 23: 1328-1341Abstract Full Text PDF PubMed Google Scholar–22Zhang L. Yan F. Zhang S. Lei D. Charles M.A. Cavigiolio G. Oda M. Krauss R.M. Weisgraber K.H. Rye K.A. et al.Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein.Nat. Chem. Biol. 2012; 8: 342-349Crossref PubMed Scopus (107) Google Scholar). Molecular forces introduced by the lipoproteins at either end of the CETP molecule cause a twisting of the CETP molecule that results in the formation of a tunnel through which cholesteryl esters are transferred from HDL to LDL or VLDL. The ternary complex then dissociates to form VLDL and LDL particles that are enriched in cholesteryl esters and HDL particles that are depleted of cholesteryl esters and thus reduced in size (22Zhang L. Yan F. Zhang S. Lei D. Charles M.A. Cavigiolio G. Oda M. Krauss R.M. Weisgraber K.H. Rye K.A. et al.Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein.Nat. Chem. Biol. 2012; 8: 342-349Crossref PubMed Scopus (107) Google Scholar). Although there is experimental evidence supporting the existence of both the shuttle and tunnel mechanisms, the extent to which either mechanism operates in vivo remains completely unknown. The first evidence that CETP activity affects plasma lipoproteins was provided by observations in people with genetic deficiencies of CETP. The first CETP mutation was identified in Japan in 1989 as a cause of markedly elevated HDL-C. Ten mutations associated with CETP deficiency have since been identified in Asians and one in Caucasians. It was found in Japan that 57% of subjects with levels of HDL-C greater than 100 mg/dl have mutations of the CETP gene. In addition, 37% of Japanese with levels HDL-C between 75 and 100 mg/dl have mutations of the CETP gene (24Brown M.L. Inazu A. Hesler C.B. Agellon L.B. Mann C. Whitlock M.E. Marcel Y.L. Milne R.W. Koizumi J. Mabuchi H. et al.Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins.Nature. 1989; 342: 448-451Crossref PubMed Scopus (410) Google Scholar–28Teh E.M. Dolphin P.J. Breckenridge W.C. Tan M.H. Human plasma CETP deficiency: identification of a novel mutation in exon 9 of the CETP gene in a Caucasian subject from North America.J. Lipid Res. 1998; 39: 442-456Abstract Full Text Full Text PDF PubMed Google Scholar). Similar conclusions were drawn from studies in rabbits that were treated with an anti-CETP antibody that resulted in a substantial increase in the concentration of HDL-C (29Whitlock M.E. Swenson T.L. Ramakrishnan R. Leonard M.T. Marcel Y.L. Milne R.W. Tall A.R. Monoclonal antibody inhibition of cholesteryl ester transfer protein activity in the rabbit. Effects on lipoprotein composition and high density lipoprotein cholesteryl ester metabolism.J. Clin. Invest. 1989; 84: 129-137Crossref PubMed Scopus (111) Google Scholar). Consistent with these observations in CETP-deficient patients and rabbits treated with an anti-CETP antibody, it has since been found that treatment of humans with CETP inhibitor drugs (30Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. et al.Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2605) Google Scholar–33Nicholls S.J. Brewer H.B. Kastelein J.J. Krueger K.A. Wang M.D. Shao M. Hu B. McErlean E. Nissen S.E. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial.JAMA. 2011; 306: 2099-2109Crossref PubMed Scopus (368) Google Scholar) increases the concentration of both HDL-C and apoA-I (the major apolipoprotein in HDLs) and, in some cases, also decreases the concentration of LDL-C and apoB (the main LDL apolipoprotein) over and above the effects achieved by treatment with statins. In the case of transfers of cholesteryl esters between HDLs and the much more rapidly catabolized TRLs, the amount of CETP in plasma is already rate limiting under most conditions (12Barter P.J. Hopkins G.J. Calvert G.D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins.Biochem. J. 1982; 208: 1-7Crossref PubMed Scopus (146) Google Scholar). This is apparent from the net mass transfer of cholesteryl esters from HDLs to TRLs that occurs when the two fractions are incubated in vitro in the presence of CETP (34Marcel Y.L. Vezina C. Teng B. Sniderman A. Transfer of cholesterol esters between human high density lipoproteins and triglyceride-rich lipoproteins controlled by a plasma protein factor.Atherosclerosis. 1980; 35: 127-133Abstract Full Text PDF PubMed Scopus (61) Google Scholar). It is therefore not surprising that inhibiting CETP reduces the cholesteryl ester content of TRLs (35Krauss R.M. Wojnooski K. Orr J. Geaney J.C. Pinto C.A. Liu Y. Wagner J.A. Luk J.M. Johnson-Levonas A.O. Anderson M.S. et al.Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib.J. Lipid Res. 2012; 53: 540-547Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Thus, inhibiting CETP in humans affects the concentration and composition of all lipoprotein fractions in ways that are potentially antiatherogenic. The increased concentration of HDLs that occurs with CETP inhibition has the potential to be atheroprotective by a number of mechanisms (Fig. 4). The best known of these relates to the ability of HDLs to promote the efflux of cholesterol from macrophages in the artery wall (36Johnson W.J. Phillips M.C. Rothblat G.H. Lipoproteins and cellular cholesterol homeostasis.Subcell. Biochem. 1997; 28: 235-276Crossref PubMed Scopus (28) Google Scholar). However, HDLs have several additional potentially antiatherogenic properties. 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The results in transgenic mice engineered to express CETP are conflicting and model dependent. Some of these studies in transgenic mice suggest that CETP is proatherogenic (48Westerterp M. van der Hoogt C.C. de Haan W. Offerman E.H. Dallinga-Thie G.M. Jukema J.W. Havekes L.M. Rensen P.C. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2552-2559Crossref PubMed Scopus (179) Google Scholar–50Marotti K.R. Castle C.K. Boyle T.P. Lin A.H. Murray R.W. Melchior G.W. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein.Nature. 1993; 364: 73-75Crossref PubMed Scopus (412) Google Scholar), whereas others suggest that it is antiatherogenic (51Föger B. Chase M. Amar M.J. Vaisman B.L. Shamburek R.D. Paigen B. Fruchart-Najib J. Paiz J.A. Koch C.A. Hoyt R.F. et al.Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice.J. Biol. Chem. 1999; 274: 36912-36920Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar–53Hayek T. Masucci-Magoulas L. Jiang X. Walsh A. Rubin E. Breslow J.L. Tall A.R. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.J. Clin. Invest. 1995; 96: 2071-2074Crossref PubMed Scopus (251) Google Scholar). In contrast to mice, rabbits have a high level of CETP activity (14Ha Y.C. Barter P.J. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species.Comp. Biochem. Physiol. B. 1982; 71: 265-269Crossref PubMed Scopus (46) Google Scholar) and are extremely susceptible to the development of diet-induced atherosclerosis. Furthermore, inhibiting CETP in rabbits by the use of antisense oligodeoxynucleotides (54Sugano M. Makino N. Sawada S. Otsuka S. Watanabe M. Okamoto H. Kamada M. Mizushima A. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.J. Biol. Chem. 1998; 273: 5033-5036Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar), an anti-CETP vaccine (55Rittershaus C.W. Miller D.P. Thomas L.J. Picard M.D. Honan C.M. Emmett C.D. Pettey C.L. Adari H. Hammond R.A. Beattie D.T. et al.Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2106-2112Crossref PubMed Scopus (304) Google Scholar), or by administration of small-molecule CETP inhibitors (56Okamoto H. Yonemori F. Wakitani K. Minowa T. Maeda K. Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.Nature. 2000; 406: 203-207Crossref PubMed Scopus (509) Google Scholar, 57Morehouse L.A. Sugarman E.D. Bourassa P.A. Sand T.M. Zimetti F. Gao F. Rothblat G.H. Milici A.J. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits.J. Lipid Res. 2007; 48: 1263-1272Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar) markedly reduces their susceptibility to atherosclerosis. The relationship of CETP to atherosclerosis in humans is confusing. For example, studies of the relationships between polymorphisms of the CETP gene and human atherosclerotic disease have led in some cases to the conclusion that CETP is proatherogenic, whereas in others it has been concluded that CETP is antiatherogenic. However, in a large meta-analysis of 92 studies involving 113,833 participants (58Thompson A. Di Angelantonio E. Sarwar N. Erqou S. Saleheen D. Dullaart R.P. Keavney B. Ye Z. Danesh J. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk.JAMA. 2008; 299: 2777-2788Crossref PubMed Scopus (424) Google Scholar), it was concluded that those CETP polymorphisms that are associat
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