A review of CETP and its relation to atherosclerosis

      Although the atheroprotective role of HDL cholesterol (HDL-c) is well documented, effective therapeutics to selectively increase plasma HDL-c levels are not yet available. Recent progress in unraveling human HDL metabolism has fuelled the development of strategies to decrease the incidence and progression of coronary artery disease (CAD) by raising HDL-c. In this quest for novel drugs, cholesteryl ester transfer protein (CETP) represents a pivotal target. The role of this plasma protein in HDL metabolism is highlighted by the discovery that genetic CETP deficiency is the main cause of high HDL-c levels in Asian populations. The use of CETP inhibitors to effectively increase HDL-c concentration in humans was recently published and data with regard to the effect on human atherosclerosis are expected shortly.
      This review discusses the potential of CETP inhibitors to protect against atherosclerosis in the context of the current knowledge of CETP function in both rodents and humans.
      Coronary artery disease (CAD) is the leading cause of morbidity and mortality in adults (
      • McGovern P.G.
      • Pankow J.S.
      • Shahar E.
      • Doliszny K.M.
      • Folsom A.R.
      • Blackburn H.
      • Luepker R.V.
      The Minnesota Heart Survey Investigators
      Recent trends in acute coronary heart disease-mortality, morbidity, medical care, and risk factors.
      ). Among numerous genetic and lifestyle parameters, dyslipidemia is one of the most prominent risk factors for CAD. In the past decade, lowering LDL cholesterol (LDL-c) has been the major target in cardiovascular protection strategies. This approach has proven to be beneficial and effective in both primary and secondary prevention of cardiovascular disease (CVD) (
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      ,
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • Whitney E.
      • Shapiro D.R.
      • Beere P.A.
      • Langendorfer A.
      • Stein E.A.
      • Kruyer W.
      • Gotto Jr, A.M.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      ,
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • Rouleau J.L.
      • Rutherford J.D.
      • Cole T.G.
      • Brown L.
      • Warnica J.W.
      • Arnold J.M.
      • Wun C.C.
      • Davis B.R.
      • Braunwald E.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators.
      ,
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • Isles C.G.
      • Lorimer A.R.
      • MacFarlane P.W.
      • McKillop J.H.
      • Packard C.J.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      ). Randomized studies have unequivocally shown that treatment with HMG-CoA reductase inhibitors (statins) effectively lowers LDL-c levels and reduces CAD by ∼30% (
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      ,
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • Rouleau J.L.
      • Rutherford J.D.
      • Cole T.G.
      • Brown L.
      • Warnica J.W.
      • Arnold J.M.
      • Wun C.C.
      • Davis B.R.
      • Braunwald E.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators.
      ). This same figure also points out that a large portion of cardiovascular events cannot be prevented by LDL-c lowering strategies per se; this is not surprising, given that atherosclerosis is a multifactorial disease. In the search for additional therapeutic targets, attention has recently shifted toward strategies for increasing HDL-c (
      • Gotto Jr, A.M.
      Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report.
      ), because prospective epidemiological studies have clearly shown that a low HDL-c level is a strong and independent risk factor for the development of CAD (
      • Despres J.P.
      • Lemieux I.
      • Dagenais G.R.
      • Cantin B.
      • Lamarche B.
      HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study.
      ,
      • Gordon T.
      • Castelli W.P.
      • Hjortland M.C.
      • Kannel W.B.
      • Dawber T.R.
      High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study.
      ,
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • Fye C.L.
      • Anderson J.W.
      • Elam M.B.
      • Faas F.H.
      • Linares E.
      • Schaefer E.J.
      • Schectman G.
      • Wilt T.J.
      • Wittes J.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
      ,
      • Manninen V.
      • Elo M.O.
      • Frick M.H.
      • Haapa K.
      • Heinonen O.P.
      • Heinsalmi P.
      • Helo P.
      • Huttunen J.K.
      • Kaitaniemi P.
      • Koskinen P.
      Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study.
      ).
      Attempts to elucidate the antiatherogenic effects of HDL have resulted in the discovery of a multitude of protective properties. First, HDL mediates the transport of cholesterol from the periphery (including the arterial wall) to the liver and other organs. This process of reverse cholesterol transport (RCT) is generally invoked to explain the atheroprotective effect of HDL. However, HDL also exerts antioxidative (
      • Watson A.D.
      • Berliner J.A.
      • Hama S.Y.
      • La Du B.N.
      • Faull K.F.
      • Fogelman A.M.
      • Navab M.
      Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein.
      ), antithrombotic (inhibition of platelet activation and platelet aggregation), and anti-inflammatory effects (
      • Naqvi T.Z.
      • Shah P.K.
      • Ivey P.A.
      • Molloy M.D.
      • Thomas A.M.
      • Panicker S.
      • Ahmed A.
      • Cercek B.
      • Kaul S.
      Evidence that high-density lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation.
      ,
      • Nofer J.R.
      • Kehrel B.
      • Fobker M.
      • Levkau B.
      • Assmann G.
      • Eckardstein A. von
      HDL and arteriosclerosis: beyond reverse cholesterol transport.
      ). Moreover, it has also been shown to affect endothelial function (
      • Ashby D.T.
      • Rye K.A.
      • Clay M.A.
      • Vadas M.A.
      • Gamble J.R.
      • Barter P.J.
      Factors influencing the ability of HDL to inhibit expression of vascular cell adhesion molecule-1 in endothelial cells.
      ,
      • Xia P.
      • Vadas M.A.
      • Rye K.A.
      • Barter P.J.
      • Gamble J.R.
      High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL.
      ,
      • Bisoendial R.J.
      • Hovingh G.K.
      • Levels J.H.
      • Lerch P.G.
      • Andresen I.
      • Hayden M.R.
      • Kastelein J.J.
      • Stroes E.S.
      Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein.
      ). At present, it is unclear which one or more of these hypothesized functions contribute most to the antiatherogenicity of HDL in vivo. Taken together, it is clear that HDL metabolism is very complex and the development of HDL-specific agents is elusive (
      • Stein O.
      • Stein Y.
      Atheroprotective mechanisms of HDL.
      ,
      • von Eckardstein A.
      • Nofer J.R.
      • Assmann G.
      High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport.
      ). Nevertheless, pharmaceutical inhibitors of CETP activity have recently been shown to effectively raise HDL-c levels and are therefore the focus of this review (
      • de Grooth G.J.
      • Kuivenhoven J.A.
      • Stalenhoef A.F.
      • Graaf J. de
      • Zwinderman A.H.
      • Posma J.L.
      • Tol A. van
      • Kastelein J.J.
      Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.
      ,
      • Okamoto H.
      • Yonemori F.
      • Wakitani K.
      • Minowa T.
      • Maeda K.
      • Shinkai H.
      A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
      ,
      • Clark R.W.
      • Sutfin T.A.
      • Ruggeri R.B.
      • Willauer A.T.
      • Sugarman E.D.
      • Magnus-Aryitey G.
      • Cosgrove P.G.
      • Sand T.M.
      • Wester R.T.
      • Williams J.A.
      • Perlman M.E.
      • Bamberger M.J.
      Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.
      ,
      • Brousseau M.E.
      • Schaefer E.J.
      • Wolfe M.L.
      • Bloedon L.T.
      • Digenio A.G.
      • Clark R.W.
      • Mancuso J.P.
      • Rader D.J.
      Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
      ).
      Mainly associated with the HDL particle in the circulation, CETP promotes the transfer of cholesteryl esters (CEs) from HDL to apolipoprotein B (apoB)-containing particles [i.e., very low density lipoprotein (VLDL) and LDL] in exchange for triacylglycerols (
      • Barter P.J.
      Hugh Sinclair Lecture: the regulation and remodelling of HDL by plasma factors.
      ). The protein is produced in both the liver and adipose tissue, but little knowledge exists as to why it is specifically produced in these organs. With respect to the antiatherogenicity of this transfer protein, CETP can be seen as a facilitator of cholesterol flux through the RCT system. Through its action, CE (derived from HDL) can be taken up by the liver through receptor-mediated uptake of apoB-containing lipoproteins. However, this action also directly relates to decreased HDL-c levels, which can be regarded as atherogenic. Despite the uncertainties surrounding the pro- or antiatherogenic role of CETP, inhibitors of this transfer protein are in an advanced stage of clinical development. At writing, two CETP inhibitors were about to enter phase III trials.

      FACTORS REVIEWED

       CETP deficiency

      Since the 1980s, there have been several reports of patients in Japan with marked hypercholesterolemia due to elevated levels of HDL-c (3.9–7.8 mmol/l) (
      • Koizumi J.
      • Mabuchi H.
      • Yoshimura A.
      • Michishita I.
      • Takeda M.
      • Itoh H.
      • Sakai Y.
      • Sakai T.
      • Ueda K.
      • Takeda R.
      Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia.
      ,
      • Yamashita S.
      • Matsuzawa Y.
      • Okazaki M.
      • Kako H.
      • Yasugi T.
      • Akioka H.
      • Hirano K.
      • Tarui S.
      Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity.
      ,
      • Kurasawa T.
      • Yokoyama S.
      • Miyake Y.
      • Yamamura T.
      • Yamamoto A.
      Rate of cholesteryl ester transfer between high and low density lipoproteins in human serum and a case with decreased transfer rate in association with hyperalphalipoproteinemia.
      ,
      • Matsuzawa Y.
      • Yamashita S.
      • Kameda K.
      • Kubo M.
      • Tarui S.
      • Hara I.
      Marked hyper-HDL2-cholesterolemia associated with premature corneal opacity: a case report.
      ). Mutations in the CETP gene were identified as the molecular defect underlying this increase of HDL-c (
      • Inazu A.
      • Brown M.L.
      • Hesler C.B.
      • Agellon L.B.
      • Koizumi J.
      • Takata K.
      • Maruhama Y.
      • Mabuchi H.
      • Tall A.R.
      Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
      ). Subsequent studies of lipids and lipoprotein metabolism in these individuals have provided crucial information on the role of CETP as well as the routes of human cholesterol transport in the circulation. First, a loss of CETP was shown to affect most lipoprotein classes. In complete absence of CETP function, the failure to transfer CE from HDL to other lipoproteins leads to an accumulation of CE in the HDL fraction. To accommodate the increased amounts of core lipids in HDL, other surface components such as apoAI, phospholipids, and unesterified cholesterol are also increased. Note that apoAI and apoAII concentrations increase mainly due to reduced catabolic rates, whereas the synthesis of both apolipoproteins has been reported to be unaltered (
      • Ikewaki K.
      • Rader D.J.
      • Sakamoto T.
      • Nishiwaki M.
      • Wakimoto N.
      • Schaefer J.R.
      • Ishikawa T.
      • Fairwell T.
      • Zech L.A.
      • Nakamura H.
      Delayed catabolism of high density lipoprotein apolipoproteins A-I and A-II in human cholesteryl ester transfer protein deficiency.
      ). In addition to the striking elevation of HDL-c in homozygotes for CETP gene defects, there is a substantial reduction in the concentration of LDL-c and apoB (
      • Koizumi J.
      • Mabuchi H.
      • Yoshimura A.
      • Michishita I.
      • Takeda M.
      • Itoh H.
      • Sakai Y.
      • Sakai T.
      • Ueda K.
      • Takeda R.
      Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia.
      ,
      • Yamashita S.
      • Matsuzawa Y.
      • Okazaki M.
      • Kako H.
      • Yasugi T.
      • Akioka H.
      • Hirano K.
      • Tarui S.
      Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity.
      ). These LDL particles are also small and heterogeneous and have a low affinity for the LDL-receptor (
      • Sakai N.
      • Yamashita S.
      • Hirano K.
      • Ishigami M.
      • Arai T.
      • Kobayashi K.
      • Funahashi T.
      • Matsuzawa Y.
      Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency.
      ). In contrast to apoAI and apoAII, however, the turnover of LDL and apoB is increased substantially, which has been proposed to be related to an upregulation of the LDL receptor pathway (
      • Ikewaki K.
      • Nishiwaki M.
      • Sakamoto T.
      • Ishikawa T.
      • Fairwell T.
      • Zech L.A.
      • Nagano M.
      • Nakamura H.
      • Brewer Jr., H.B.
      • Rader D.J.
      Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.
      ).

       CETP deficiency and cardiovascular risk

      In prospective epidemiological studies, an increase in HDL-c combined with a decrease in LDL-c implies a significant CAD risk reduction. However, the relationship between reduced CETP function and the susceptibility to atherosclerosis has proven complex and confusing: both longevity and increased CAD risk have been reported (
      • Koizumi J.
      • Mabuchi H.
      • Yoshimura A.
      • Michishita I.
      • Takeda M.
      • Itoh H.
      • Sakai Y.
      • Sakai T.
      • Ueda K.
      • Takeda R.
      Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia.
      ,
      • Inazu A.
      • Brown M.L.
      • Hesler C.B.
      • Agellon L.B.
      • Koizumi J.
      • Takata K.
      • Maruhama Y.
      • Mabuchi H.
      • Tall A.R.
      Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
      ,
      • Hirano K.
      • Yamashita S.
      • Nakajima N.
      • Arai T.
      • Maruyama T.
      • Yoshida Y.
      • Ishigami M.
      • Sakai N.
      • Kameda-Takemura K.
      • Matsuzawa Y.
      Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan; marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity.
      ,
      • Zhong S.
      • Sharp D.S.
      • Grove J.S.
      • Bruce C.
      • Yano K.
      • Curb J.D.
      • Tall A.R.
      Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
      ,
      • Hirano K.
      • Yamashita S.
      • Sakai N.
      • Arai T.
      • Yoshida Y.
      • Nozaki S.
      • Kameda-Takemura K.
      • Matsuzawa Y.
      Molecular defect and atherogenicity in cholesteryl ester transfer protein deficiency.
      ). Hirano and coworkers (
      • Hirano K.
      • Yamashita S.
      • Kuga Y.
      • Sakai N.
      • Nozaki S.
      • Kihara S.
      • Arai T.
      • Yanagi K.
      • Takami S.
      • Menju M.
      Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase.
      ) have shown that reduced CETP function (in 201 individuals with HDL-c levels > 2.58 mmol/l) in conjunction with reduced hepatic lipase activity is associated with an increased risk for CAD. This indicates that the metabolic setting of the individual might, at least in part, determine the ultimate effect of CETP on atherosclerosis. Furthermore, the same investigators reported that in northern Japan the prevalence of CETP deficiency was reduced in individuals over 80 years and thus was not associated with longevity (
      • Hirano K.
      • Yamashita S.
      • Nakajima N.
      • Arai T.
      • Maruyama T.
      • Yoshida Y.
      • Ishigami M.
      • Sakai N.
      • Kameda-Takemura K.
      • Matsuzawa Y.
      Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan; marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity.
      ).
      In 3,469 men of Japanese ancestry (present in the Honolulu Heart Program) with two different CETP gene mutations, the relationship between CETP deficiency and CAD was modified by HDL-c levels. It was shown that male heterozygotes for CETP gene defects with low or moderately increased HDL-c levels (1.0–1.6 mmol/l) had an increased risk for coronary heart disease, compared with men with similar HDL levels without CETP gene mutations. By contrast, men with or without CETP gene defects but with markedly elevated levels of HDL-c (>1.6 mmol/l) had less coronary heart disease (
      • Zhong S.
      • Sharp D.S.
      • Grove J.S.
      • Bruce C.
      • Yano K.
      • Curb J.D.
      • Tall A.R.
      Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
      ). Nonetheless, this ongoing prospective study with a seven-year follow-up to date recently provided further insight that heterozygotes for CETP gene defects are not at increased risk (
      • Barter P.J.
      • Brewer Jr., H.B.
      • Chapman M.J.
      • Hennekens C.H.
      • Rader D.J.
      • Tall A.R.
      Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.
      ), which is in line with earlier data on homozygous CETP deficiency (
      • Inazu A.
      • Brown M.L.
      • Hesler C.B.
      • Agellon L.B.
      • Koizumi J.
      • Takata K.
      • Maruhama Y.
      • Mabuchi H.
      • Tall A.R.
      Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
      ). Moreover, Moriyama et al. (
      • Moriyama Y.
      • Okamura T.
      • Inazu A.
      • Doi M.
      • Iso H.
      • Mouri Y.
      • Ishikawa Y.
      • Suzuki H.
      • Iida M.
      • Koizumi J.
      • Mabuchi H.
      • Komachi Y.
      A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency.
      ) reported the outcome of a cross-sectional analysis in a population with 19,044 male and 29,487 female Japanese subjects, in which subjects with very high HDL-c levels, as well as subjects with mild-to-moderate HDL-c elevation, appear to be protected against CVD, regardless of CETP status. Summarizing, the relation between human CETP deficiencies, either in homozygous or heterozygous form, and the risk of CVD remains a matter of debate.

       CETP gene polymorphisms and cardiovascular risk

      Studying common CETP gene variants has not, unfortunately, provided a clear insight into the relationship between CETP and atherosclerosis. Of these, the TaqIB polymorphism located in intron 1 of the CETP gene is one of the most intensively studied (
      • Bernard S.
      • Moulin P.
      • Lagrost L.
      • Picard S.
      • Elchebly M.
      • Ponsin G.
      • Chapuis F.
      • Berthezene F.
      Association between plasma HDL-cholesterol concentration and Taq1B CETP gene polymorphism in non-insulin-dependent diabetes mellitus.
      ,
      • Brousseau M.E.
      • O'Connor Jr., J.J.
      • Ordovas J.M.
      • Collins D.
      • Otvos J.D.
      • Massov T.
      • McNamara J.R.
      • Rubins H.B.
      • Robins S.J.
      • Schaefer E.J.
      Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.
      ,
      • Freeman D.J.
      • Griffin B.A.
      • Holmes A.P.
      • Lindsay G.M.
      • Gaffney D.
      • Packard C.J.
      • Shepherd J.
      Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors: associations between the TaqI B RFLP in the CETP gene and smoking and obesity.
      ,
      • Kuivenhoven J.A.
      • Knijff P. de
      • Boer J.M.
      • Smalheer H.A.
      • Botma G.J.
      • Seidell J.C.
      • Kastelein J.J.
      • Pritchard P.H.
      Heterogeneity at the CETP gene locus: influence on plasma CETP concentrations and HDL cholesterol levels.
      ,
      • Liu S.
      • Schmitz C.
      • Stampfer M.J.
      • Sacks F.
      • Hennekens C.H.
      • Lindpaintner K.
      • Ridker P.M.
      A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men.
      ,
      • Ordovas J.M.
      • Cupples L.A.
      • Corella D.
      • Otvos J.D.
      • Osgood D.
      • Martinez A.
      • Lahoz C.
      • Coltell O.
      • Wilson P.W.
      • Schaefer E.J.
      Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study.
      ,
      • van Venrooij F.V.
      • Stolk R.P.
      • Banga J.D.
      • Sijmonsma T.P.
      • Tol A. van
      • Erkelens D.W.
      • Dallinga-Thie G.M.
      Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes.
      ,
      • Kuivenhoven J.A.
      • Jukema J.W.
      • Zwinderman A.H.
      • Knijff P. de
      • McPherson R.
      • Bruschke A.V.
      • Lie K.I.
      • Kastelein J.J.
      The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group.
      ). The associations of TaqIB with various parameters is generally thought to arise from strong linkage disequilibrium between TaqIB and the -C629A polymorphism, of which the latter has been shown to directly affect CETP promoter activity (
      • Dachet C.
      • Poirier O.
      • Cambien F.
      • Chapman J.
      • Rouis M.
      New functional promoter polymorphism, CETP/-629, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels: role of Sp1/Sp3 in transcriptional regulation.
      ,
      • Boekholdt S.M.
      • Thompson J.F.
      Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease.
      ,
      • Klerkx A.H.
      • Tanck M.W.
      • Kastelein J.J.
      • Molhuizen H.O.
      • Jukema J.W.
      • Zwinderman A.H.
      • Kuivenhoven J.A.
      Haplotype analysis of the CETP gene: not TaqIB, but the closely linked -629C→A polymorphism and a novel promoter variant are independently associated with CETP concentration.
      ). Significant associations of the B1B1 genotype with higher plasma CETP concentration and/or CETP activity and lower HDL-c levels were found in several studies (
      • Ordovas J.M.
      • Cupples L.A.
      • Corella D.
      • Otvos J.D.
      • Osgood D.
      • Martinez A.
      • Lahoz C.
      • Coltell O.
      • Wilson P.W.
      • Schaefer E.J.
      Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study.
      ,
      • Kuivenhoven J.A.
      • Jukema J.W.
      • Zwinderman A.H.
      • Knijff P. de
      • McPherson R.
      • Bruschke A.V.
      • Lie K.I.
      • Kastelein J.J.
      The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group.
      ,
      • Corbex M.
      • Poirier O.
      • Fumeron F.
      • Betoulle D.
      • Evans A.
      • Ruidavets J.B.
      • Arveiler D.
      • Luc G.
      • Tiret L.
      • Cambien F.
      Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction.
      ,
      • Corella D.
      • Saiz C.
      • Guillen M.
      • Portoles O.
      • Mulet F.
      • Gonzalez J.I.
      • Ordovas J.M.
      Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population.
      ,
      • Klerkx A.H.E.M.
      • de Grooth G.J.
      • Zwinderman A.H.
      • Jukema J.W.
      • Kuivenhoven J.A.
      • Kastelein J.J.P.
      Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS).
      ), but this was not consistently observed (
      • Freeman D.J.
      • Griffin B.A.
      • Holmes A.P.
      • Lindsay G.M.
      • Gaffney D.
      • Packard C.J.
      • Shepherd J.
      Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors: associations between the TaqI B RFLP in the CETP gene and smoking and obesity.
      ,
      • Goto A.
      • Sasai K.
      • Suzuki S.
      • Fukutomi T.
      • Ito S.
      • Matsushita T.
      • Okamoto M.
      • Suzuki T.
      • Itoh M.
      • Okumura-Noji K.
      • Yokoyama S.
      Cholesteryl ester transfer protein and atherosclerosis in Japanese subjects: a study based on coronary angiography.
      ,
      • Kakko S.
      • Tamminen M.
      • Paivansalo M.
      • Kauma H.
      • Rantala A.O.
      • Lilja M.
      • Reunanen A.
      • Kesaniemi Y.A.
      • Savolainen M.J.
      Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima-media thickness.
      ,
      • Meguro S.
      • Takei I.
      • Murata M.
      • Hirose H.
      • Takei N.
      • Mitsuyoshi Y.
      • Ishii K.
      • Oguchi S.
      • Shinohara J.
      • Takeshita E.
      • Watanabe K.
      • Saruta T.
      Cholesteryl ester transfer protein polymorphism associated with macroangiopathy in Japanese patients with type 2 diabetes.
      ). Furthermore, it has been reported that the effects of TaqIB on the above parameters are gender-dependent and also influenced by alcohol use, body mass index, and insulin levels (
      • Freeman D.J.
      • Griffin B.A.
      • Holmes A.P.
      • Lindsay G.M.
      • Gaffney D.
      • Packard C.J.
      • Shepherd J.
      Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors: associations between the TaqI B RFLP in the CETP gene and smoking and obesity.
      ,
      • Ordovas J.M.
      • Cupples L.A.
      • Corella D.
      • Otvos J.D.
      • Osgood D.
      • Martinez A.
      • Lahoz C.
      • Coltell O.
      • Wilson P.W.
      • Schaefer E.J.
      Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study.
      ,
      • Corbex M.
      • Poirier O.
      • Fumeron F.
      • Betoulle D.
      • Evans A.
      • Ruidavets J.B.
      • Arveiler D.
      • Luc G.
      • Tiret L.
      • Cambien F.
      Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction.
      ,
      • Hannuksela M.
      • Marcel Y.L.
      • Kesaniemi Y.A.
      • Savolainen M.J.
      Reduction in the concentration and activity of plasma cholesteryl ester transfer protein by alcohol.
      ,
      • Fumeron F.
      • Betoulle D.
      • Luc G.
      • Behague I.
      • Ricard S.
      • Poirier O.
      • Jemaa R.
      • Evans A.
      • Arveiler D.
      • Marques-Vidal P.
      Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction.
      ,
      • Vohl M.C.
      • Lamarche B.
      • Pascot A.
      • Leroux G.
      • Prud'homme D.
      • Bouchard C.
      • Nadeau A.
      • Despres J.P.
      Contribution of the cholesteryl ester transfer protein gene TaqIB polymorphism to the reduced plasma HDL-cholesterol levels found in abdominal obese men with the features of the insulin resistance syndrome.
      ). Despite the fact that HDL-c and CETP function are modulated by multiple genetic and environmental factors, and given that HDL only partly determines the risk for atherosclerosis, this single genetic marker has indeed been shown to be associated with CAD risk. In the Framingham Offspring Study, the B2 allele was associated with a reduced risk of coronary heart disease in men (
      • Ordovas J.M.
      • Cupples L.A.
      • Corella D.
      • Otvos J.D.
      • Osgood D.
      • Martinez A.
      • Lahoz C.
      • Coltell O.
      • Wilson P.W.
      • Schaefer E.J.
      Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study.
      ), and recently this was confirmed in the Veterans Affair HDL-c Intervention Trial (
      • Brousseau M.E.
      • O'Connor Jr., J.J.
      • Ordovas J.M.
      • Collins D.
      • Otvos J.D.
      • Massov T.
      • McNamara J.R.
      • Rubins H.B.
      • Robins S.J.
      • Schaefer E.J.
      Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.
      ) and in WOSCOPS (
      • Freeman D.J.
      • Samani N.J.
      • Wilson V.
      • McMahon A.D.
      • Braund P.S.
      • Cheng S.
      • Caslake M.J.
      • Packard C.J.
      • Gaffney D.
      A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study.
      ). Moreover, in a prospective follow-up study of 1,211 CAD patients (AtheroGene Study), the A allele of the CETP -629 promoter polymorphism (in strong linkage disequilibrium with TaqIB B2 allele) was found to be associated with decreased mortality from cardiovascular events (
      • Blankenberg S.
      • Rupprecht H.J.
      • Bickel C.
      • Jiang X.C.
      • Poirier O.
      • Lackner K.J.
      • Meyer J.
      • Cambien F.
      • Tiret L.
      Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease.
      ). On the contrary, in men and women with a history of myocardial infarction (Coronary and Recurrent Events Study) (
      • de Grooth G.J.
      • Zerba K.E.
      • Huang S.
      • Tsuchihashi Z.
      • Kirchgessner T.
      • Belder R.
      • Vishnupad V.
      • Hu B.
      • Klerkx A.H.E.M.
      • Zwinderman A.H.
      • Jukema J.W.
      • Sacks F.
      • Kastelein J.J.P.
      • Kuivenhoven J.A.
      The cholesteryl ester transfer protein (CETP) TaqIB polymorphism in the Cholesterol And Recurrent Events study (CARE): no interaction with the response to pravastatin therapy and no effects on cardiovascular outcome.
      ) and in a cohort of healthy middle-aged U.S. physicians (
      • Liu S.
      • Schmitz C.
      • Stampfer M.J.
      • Sacks F.
      • Hennekens C.H.
      • Lindpaintner K.
      • Ridker P.M.
      A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men.
      ), no association was found between TaqIB genotype and coronary heart disease.
      Recently, other investigators showed that a less frequent CETP polymorphism, which results in the exchange of an isoleucine to a valine at position 405, is associated with longevity (
      • Barzilai N.
      • Atzmon G.
      • Schechter C.
      • Schaefer E.J.
      • Cupples A.L.
      • Lipton R.
      • Cheng S.
      • Shuldiner A.R.
      Unique lipoprotein phenotype and genotype associated with exceptional longevity.
      ) and low CETP concentration (
      • Bruce C.
      • Sharp D.S.
      • Tall A.R.
      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.
      ). However, in hypertriglyceridemia men (>1.9 mmol/l), this variant was found to be associated with increased prevalence of coronary heart disease despite elevated HDL-c (
      • Bruce C.
      • Sharp D.S.
      • Tall A.R.
      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.
      ). This again might imply that CETP can either be pro- or antiatherogenic, depending on the metabolic setting. Thus, the association between CETP genotype and CAD is unclear. In this context, it is not surprising that single CETP gene markers may not be powerful enough to predict the progression of a complex chronic disease such as atherosclerosis.

       CETP and dyslipidemia, which comes first?

      In various human dyslipidemias associated with accelerated atherosclerosis, CETP concentration and/or the rate of net transfer of CE from HDL to apoB-containing lipoproteins is increased, as recently reviewed in detail by Le Goff et al. (
      • Le Goff W.
      • Guerin M.
      • Chapman M.J.
      Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia.
      ). Briefly, plasma CETP was found to be increased in individuals with hypercholesterolemia (
      • Bagdade J.D.
      • Ritter M.C.
      • Subbaiah P.V.
      Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia.
      ,
      • McPherson R.
      • Mann C.J.
      • Tall A.R.
      • Hogue M.
      • Martin L.
      • Milne R.W.
      • Marcel Y.L.
      Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables.
      ,
      • Sparks D.L.
      • Frohlich J.
      • Lacko A.G.
      • Pritchard P.H.
      Relationship between cholesteryl ester transfer activity and high density lipoprotein composition in hyperlipidemic patients.
      ,
      • de Grooth G.J.
      • Smilde T.J.
      • Wissen S. van
      • Klerkx A.H.E.M.
      • Zwinderman A.H.
      • Fruchart J.C.
      • Kastelein J.J.P.
      • Stalenhoef A.F.H.
      • Kuivenhoven J.A.
      The relationship between cholesteryl ester transfer protein levels and risk factors in patients with familial hypercholesterolemia.
      ), combined hyperlipidemia, dysbetalipoprotemia (
      • Tall A.
      • Granot E.
      • Brocia R.
      • Tabas I.
      • Hesler C.
      • Williams K.
      • Denke M.
      Accelerated transfer of cholesteryl esters in dyslipidemic plasma: role of cholesteryl ester transfer protein.
      ), severe chylomicronemia (
      • McPherson R.
      • Mann C.J.
      • Tall A.R.
      • Hogue M.
      • Martin L.
      • Milne R.W.
      • Marcel Y.L.
      Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables.
      ), and nephrotic syndrome (
      • Moulin P.
      • Appel G.B.
      • Ginsberg H.N.
      • Tall A.R.
      Increased concentration of plasma cholesteryl ester transfer protein in nephrotic syndrome: role in dyslipidemia.
      ). This might imply that CETP is deleterious, but it can also be argued that high CETP is the result rather than the cause of dyslipidemia (
      • van Tol A.
      CETP-catalysed transfer of cholesterylesters from HDL to apo B-containing lipoproteins in plasma from diabetic patients (Letter).
      ). In this regard, CETP action itself is directed by the composition of various lipoproteins. Lifestyle factors further complicate this issue: it has been described that alcohol abuse and physical exercise, typically associated with increased HDL-c, are associated with diminished CETP concentration (
      • Hannuksela M.
      • Marcel Y.L.
      • Kesaniemi Y.A.
      • Savolainen M.J.
      Reduction in the concentration and activity of plasma cholesteryl ester transfer protein by alcohol.
      ,
      • Savolainen M.J.
      • Hannuksela M.
      • Seppanen S.
      • Kervinen K.
      • Kesaniemi Y.A.
      Increased high-density lipoprotein cholesterol concentration in alcoholics is related to low cholesteryl ester transfer protein activity.
      ,
      • Seip R.L.
      • Moulin P.
      • Cocke T.
      • Tall A.
      • Kohrt W.M.
      • Mankowitz K.
      • Semenkovich C.F.
      • Ostlund R.
      • Schonfeld G.
      Exercise training decreases plasma cholesteryl ester transfer protein.
      ). Similarly, smoking (associated with low HDL-c) is associated with high CETP activity (
      • Dullaart R.P.
      • Hoogenberg K.
      • Dikkeschei B.D.
      • Tol A. van
      Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men.
      ,
      • Freeman D.J.
      • Griffin B.A.
      • Murray E.
      • Lindsay G.M.
      • Gaffney D.
      • Packard C.J.
      • Shepherd J.
      Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution.
      ). A cross-sectional study showed an inverse relation between CETP and HDL-c among hypertriacylglycerolemic but not normotriacylglycerolemic men (
      • Foger B.
      • Ritsch A.
      • Doblinger A.
      • Wessels H.
      • Patsch J.R.
      Relationship of plasma cholesteryl ester transfer protein to HDL cholesterol: studies in normotriglyceridemia and moderate hypertriglyceridemia.
      ). These studies clearly indicate that plasma CETP is affected by a variety of metabolic conditions and lifestyle factors that are in themselves associated with changes in CAD risk.

       CETP in animals

      Mice and rats, naturally CETP deficient, use HDL as the major means of cholesterol transport in the circulation. In accord with the discussed antiatherogenic potential of this lipoprotein, these rodents are relatively resistant to atherosclerosis. On the other hand, rabbits (with naturally high CETP levels) transport most of their cholesterol in LDL and are susceptible to atherosclerosis (
      • Tall A.R.
      Plasma lipid transfer proteins.
      ). This brings us to humans, who express CETP, transport their cholesterol mainly in LDL, and also (especially in the Western world) are susceptible to atherosclerosis. Of course, human susceptibility to atherosclerosis is also strongly related to deleterious lifestyle parameters, such as high fat intake, smoking, and lack of physical exercise, but CETP-expressing mammals do appear to be predisposed to atherosclerosis.
      Genetically engineered mice have proven to be valid models for the study of CETP function and its relation with atherosclerosis. Introduction of the human CETP gene into mice results in a dose-related reduction of HDL-c levels and, as a consequence, these animals have significantly more early atherosclerotic lesions in the proximal aorta than do control mice (
      • Marotti 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.
      ). Subsequent crossbreeding with apoE- and LDL-receptor knockout mice further underscores the finding that high levels of human CETP accelerate lesion development (
      • Plump A.S.
      • Masucci-Magoulas L.
      • Bruce C.
      • Bisgaier C.L.
      • Breslow J.L.
      • Tall A.R.
      Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression.
      ). In contrast, in the setting of hypertriacylglycerolemia, CETP expression was antiatherogenic (
      • Hayek 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.
      ). In addition, CETP expression was found to reduce atherosclerosis in (human) LCAT transgenic mice by correcting the dysfunctional properties of HDL and promoting the hepatic uptake of HDL-CE (
      • Foger 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.
      • Brewer Jr., H.B.
      • Santamarina-Fojo S.
      Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice.
      ). Summarizing, studies in mice have shown that expression or overexpression of human CETP in the context of a compromised liver-mediated uptake of atherogenic lipoproteins is deleterious, but that in the presence of high concentration of triacylglycerols and dysfunctional HDL, CETP can also have antiatherogenic effects.

       CETP inhibition in animals

      Various strategies have been developed to inhibit CETP activity in the circulation. Here we first discuss the effects on lipids with a subsequent focus on atherosclerosis. In 1989, Whitlock et al. (
      • Whitlock 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.
      ) were among the first to effectively inhibit CETP in vivo. Intravenous injection of monoclonal antibodies raised against CETP was used to investigate the effect of CETP on lipoprotein composition in rabbits. From these experiments, it was concluded that CETP plays an important role in the clearance of CE from plasma (
      • Whitlock 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.
      ,
      • Abbey M.
      • Calvert G.D.
      Effects of blocking plasma lipid transfer protein activity in the rabbit.
      ). Furthermore, the use of CETP antibodies in hamsters was also effective in raising HDL-c (33%) (
      • Gaynor B.J.
      • Sand T.
      • Clark R.W.
      • Aiello R.J.
      • Bamberger M.J.
      • Moberly J.B.
      Inhibition of cholesteryl ester transfer protein activity in hamsters alters HDL lipid composition.
      ) and was shown to induce effects on lipoproteins similar to those reported in human CETP deficiency (
      • Evans G.F.
      • Bensch W.R.
      • Apelgren L.D.
      • Bailey D.
      • Kauffman R.F.
      • Bumol T.F.
      • Zuckerman S.H.
      Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution.
      ). In addition to these immunological approaches, several synthetic CETP inhibitors have also been developed. One of the first inhibitors, CGS25159, induced significant decreases in VLDL-c and VLDL-triacylglycerols levels on top of an increase of HDL-c (29%) in normal and hyperlipidemic hamsters at 30 mg/kg/day dosages (
      • Kothari H.V.
      • Poirier K.J.
      • Lee W.H.
      • Satoh Y.
      Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters.
      ). In 2000, JTT-705, another synthetic CETP inhibitor, was reported to achieve a 50% inhibition of CETP activity in human plasma in vitro at a concentration of 5 μM (
      • Shinkai H.
      • Maeda K.
      • Yamasaki T.
      • Okamoto H.
      • Uchida I.
      bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein.
      ). A 95% inhibition of CETP activity was reached in rabbit plasma after administering this compound at an oral dose of 30 mg/kg. In addition, the effects of JTT-705 were compared with the effects of simvastatin in these rabbits. Both JTT-705 and simvastatin caused an increase in HDL-c (90% and 28%, respectively) and a decrease of nonHDL-c (40–50% and 50–70%, respectively) (
      • Okamoto H.
      • Yonemori F.
      • Wakitani K.
      • Minowa T.
      • Maeda K.
      • Shinkai H.
      A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
      ). Finally, a vaccine eliciting antibodies that block CETP function was also shown to induce a significant increase of HDL-c and a modest decrease of LDL-c concentration (
      • Rittershaus 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.
      • Callow A.D.
      • Marsh H.C.
      • Ryan U.S.
      Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.
      ).
      Beyond lipid modulation, a few promising studies have been published that were conducted primarily in cholesterol-fed rabbits (
      • Okamoto H.
      • Yonemori F.
      • Wakitani K.
      • Minowa T.
      • Maeda K.
      • Shinkai H.
      A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
      ,
      • Rittershaus 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.
      • Callow A.D.
      • Marsh H.C.
      • Ryan U.S.
      Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.
      ,
      • Huang Z.
      • Inazu A.
      • Nohara A.
      • Higashikata T.
      • Mabuchi H.
      Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.
      ,
      • Sugano 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.
      ), a model for diet-induced atherosclerosis that closely mimics human atherosclerosis. CETP inhibition in this animal model (achieved through antisense oligonucleotides, vaccine-induced CETP antibodies, or the chemical CETP-inhibitor JTT-705) led to increased HDL-c levels (35, 42, and 90%, respectively) with concomitant antiatherogenic effects (
      • Okamoto H.
      • Yonemori F.
      • Wakitani K.
      • Minowa T.
      • Maeda K.
      • Shinkai H.
      A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
      ,
      • Rittershaus 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.
      • Callow A.D.
      • Marsh H.C.
      • Ryan U.S.
      Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.
      ,
      • Sugano 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.
      ). In these studies, atherosclerotic lesions were reduced by 7, 40, and 70%, respectively, compared with control cholesterol-fed rabbits. In a direct comparison with a typical LDL-c lowering drug (simvastatin), JTT-705 reduced the area of atherosclerotic lesions to a similar extent (reduced by 80%) (
      • Okamoto H.
      • Yonemori F.
      • Wakitani K.
      • Minowa T.
      • Maeda K.
      • Shinkai H.
      A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
      ). Nevertheless, in rabbits with very severe hypercholesterolemia (total cholesterol 10.5 mmol/l, compared with 6.8 mmol/l; induced by adding more cholesterol to their diet) who were treated with various dosages of this CETP inhibitor, no effect was seen on aortic cholesterol content despite a 70% inhibition of CETP activity and a concomitant 200% increase of HDL-c levels. Unexpectedly, however, triacylglycerol levels increased in these animals, which may explain why there was no effect on atherosclerosis (
      • Huang Z.
      • Inazu A.
      • Nohara A.
      • Higashikata T.
      • Mabuchi H.
      Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.
      ).

       CETP inhibitors in humans

      Data on pharmaceutical inhibition of CETP in humans is limited to two small molecule inhibitors, JTT-705 (
      • de Grooth G.J.
      • Kuivenhoven J.A.
      • Stalenhoef A.F.
      • Graaf J. de
      • Zwinderman A.H.
      • Posma J.L.
      • Tol A. van
      • Kastelein J.J.
      Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.
      ) and torcetrapib (
      • Clark R.W.
      • Sutfin T.A.
      • Ruggeri R.B.
      • Willauer A.T.
      • Sugarman E.D.
      • Magnus-Aryitey G.
      • Cosgrove P.G.
      • Sand T.M.
      • Wester R.T.
      • Williams J.A.
      • Perlman M.E.
      • Bamberger M.J.
      Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.
      ,
      • Brousseau M.E.
      • Schaefer E.J.
      • Wolfe M.L.
      • Bloedon L.T.
      • Digenio A.G.
      • Clark R.W.
      • Mancuso J.P.
      • Rader D.J.
      Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
      ). JTT-705 was initially tested in a single-dose study (100–1,800 mg), which showed that the drug was well tolerated and did not result in significant toxicity in healthy Caucasian men. A two-period crossover bioavailability study revealed that the drug induced a more pronounced CETP inhibition in the postprandial phase compared with the fasted state. In a subsequent randomized, double-blind, and placebo-controlled phase II trial, JTT-705 was tested on 198 healthy subjects with mild hyperlipidemia for 4 weeks. At the highest dose, JTT-705 led to a 34% increase in HDL-c and a 7% decrease in LDL-c. The drug proved safe and was well tolerated, and no adverse events related to the use of the drug were reported (
      • de Grooth G.J.
      • Kuivenhoven J.A.
      • Stalenhoef A.F.
      • Graaf J. de
      • Zwinderman A.H.
      • Posma J.L.
      • Tol A. van
      • Kastelein J.J.
      Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.
      ).
      In a recent 14 day dose-finding study, the second investigational drug, torcetrapib, was tested in 30 healthy young individuals, with 10 individuals given placebo (
      • Clark R.W.
      • Sutfin T.A.
      • Ruggeri R.B.
      • Willauer A.T.
      • Sugarman E.D.
      • Magnus-Aryitey G.
      • Cosgrove P.G.
      • Sand T.M.
      • Wester R.T.
      • Williams J.A.
      • Perlman M.E.
      • Bamberger M.J.
      Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.
      ). Dosages ranging from 10 mg to 240 mg daily were well tolerated and led to elevations of plasma HDL-c of 16% to 91%, indicating that torcetrapib exhibits stronger HDL-c-increasing effects than JTT-705. Like JTT-705, torcetrapib also lowered LDL-c levels but to a greater extent; reductions of 21% and 42% were noted at the higher doses.
      Comparing these results of JTT-705 or torcetrapib monotherapy reveals an intriguing difference. JTT-705 at 900 mg daily was previously shown to raise HDL-c by 34% upon a 37% reduction of CETP activity levels in subject with mild dyslipidemia (HDL-c: 1.17 mmol/l) (
      • de Grooth G.J.
      • Kuivenhoven J.A.
      • Stalenhoef A.F.
      • Graaf J. de
      • Zwinderman A.H.
      • Posma J.L.
      • Tol A. van
      • Kastelein J.J.
      Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study.
      ). In individuals with low baseline HDL-c (1.01 mmol/l), 120 mg torcetrapib daily, however, induced a 46% increase of HDL-c with only 28% CETP inhibition. Thus, the percentage CETP inhibition needed to raise HDL-c by 1% was 0.61% in the torcetrapib-treated individuals but 1.09% in the JTT-705-treated individuals. Perhaps these data teach us that CETP inhibition is more effective for increasing HDL-c in low HDL-c individuals than in subjects with relatively normal HDL-c levels, an issue that needs further investigation.
      In a second study, 120 mg of torcetrapib proved safe and effective when used in combination with 20 mg of the LDL-c lowering drug atorvastatin in nine individuals with low HDL-c (<1.0 mmol/l). This is important, considering that in clinical practice HDL-c increasing therapy is likely to be used in combination with evidence-based LDL-c-lowering medication. This study again underscored the potency of this drug to reduce LDL-c levels: in six individuals who used 120 mg torcetrapib twice daily LDL-c was reduced by 17%. A similar reduction was achieved in nine individuals who received the combination treatment.
      In addition to their HDL-c increasing potential, JTT-705 and torcetrapib share the absence of effect on plasma triacylglycerol levels (moderate at the highest dosages of torcetrapib). It will be of interest how these investigational drugs will modulate lipids and lipoproteins in hypertriacylglycerolemic individuals, an issue further addressed below. Another notable finding is that both inhibitors cause a marked increase in plasma CETP concentration. Clark et al. (
      • Clark R.W.
      • Sutfin T.A.
      • Ruggeri R.B.
      • Willauer A.T.
      • Sugarman E.D.
      • Magnus-Aryitey G.
      • Cosgrove P.G.
      • Sand T.M.
      • Wester R.T.
      • Williams J.A.
      • Perlman M.E.
      • Bamberger M.J.
      Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.
      ) suggested that this is the result of an inhibitor-induced complex formation between CETP and HDL. Although this complex formation was not assumed to affect HDL function, the biological properties of the markedly changed HDL pool, complexed with CETP inhibitors or not, have not been addressed to date. In addition, there is no mention of the effects of CETP inhibitors on the excretion of cholesterol and bile acids as a final step in proposed RCT pathway.
      In summary, these data clearly show that CETP inhibition effectively raises HDL-c levels without serious side effects in healthy individuals with mild dyslipidemia and low HDL-c levels. In addition, torcetrapib was safe and effective when combined with LDL-c-lowering medication, although these data are restricted to only nine individuals with low HDL-c.

      CONSIDERATIONS

      This review inevitably underscores the complexity of the relationships among CETP, HDL, and atherosclerosis. On the basis of human and animal studies, we conclude that the role of CETP in atherogenesis is likely dependent on the metabolic, genetic, and environmental context. Lowering CETP activity may be beneficial in an affluent environment, where high-fat and cholesterol-rich diets increase plasma LDL-c levels and downregulate hepatic LDL receptors (
      • Applebaum-Bowden D.
      • Haffner S.M.
      • Hartsook E.
      • Luk K.H.
      • Albers J.J.
      • Hazzard W.R.
      Down-regulation of the low-density lipoprotein receptor by dietary cholesterol.
      ). However, interfering with RCT by inhibition of CETP, a protein at the intersection of HDL and LDL metabolism, will undoubtedly have multiple effects, the consequences of which are currently unknown. CETP inhibition will likely force delivery of cholesterol through HDL to the liver. In the presence of fully functional HDL-c uptake mechanisms, this may be more desirable than uploading atherogenic LDL particles with even more CE from HDL. However, it should be realized that very little is known about the function and the capacity of the scavenger receptor class B type 1 in humans (
      • Acton S.
      • Osgood D.
      • Donoghue M.
      • Corella D.
      • Pocovi M.
      • Cenarro A.
      • Mozas P.
      • Keilty J.
      • Squazzo S.
      • Woolf E.A.
      • Ordovas J.M.
      Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population.
      ,
      • Osgood D.
      • Corella D.
      • Demissie S.
      • Cupples L.A.
      • Wilson P.W.
      • Meigs J.B.
      • Schaefer E.J.
      • Coltell O.
      • Ordovas J.M.
      Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: the Framingham Study.
      ), a receptor that in mice mediates selective uptake of CE from HDL (
      • Acton S.
      • Rigotti A.
      • Landschulz K.T.
      • Xu S.
      • Hobbs H.H.
      • Krieger M.
      Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.
      ). It remains to be elucidated how the uptake of HDL-associated lipids by the liver and/or other organs is truly controlled in humans. This is important when considering that CETP inhibition will result in the accumulation of large CE-enriched HDL particles. It should also be considered that CETP inhibition may affect the regeneration of lipid-poor apoAI, as was recently reviewed by Rye and Barter (
      • Rye K.A.
      • Barter P.J.
      Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I.
      ). This molecule is thought important for the initial steps in RCT pathway as mediated by the ATP binding cassette A1 transmembrane protein. Whether this effect is counteracted by an increased apoAI synthesis rate, as observed after treating rabbits with a CETP inhibitor, remains to be established (
      • Shimoji E.
      • Zhang B.
      • Fan P.
      • Saku K.
      Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits.
      ). Another aspect that needs further clarification is the effect of CETP inhibition on the concentration of small dense LDL, an atherogenic lipoprotein subfraction (
      • Carmena R.
      • Duriez P.
      • Fruchart J.C.
      Atherogenic lipoprotein particles in atherosclerosis.
      ). In this regard, Yamashita et al. (
      • Yamashita S.
      • Matsuzawa Y.
      • Okazaki M.
      • Kako H.
      • Yasugi T.
      • Akioka H.
      • Hirano K.
      • Tarui S.
      Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity.
      ) have reported elevated levels of small dense LDL in CETP-deficient individuals; others have also noted the presence of additional smaller LDL fractions in these subjects (
      • Sakai N.
      • Matsuzawa Y.
      • Hirano K.
      • Yamashita S.
      • Nozaki S.
      • Ueyama Y.
      • Kubo M.
      • Tarui S.
      Detection of two species of low density lipoprotein particles in cholesteryl ester transfer protein deficiency.
      ).
      Altogether, it is premature to predict the effects of CETP inhibition on CAD risk reduction in humans. Large double-blinded, placebo-controlled trials are needed to test the efficacy of CETP inhibitors to reduce atherosclerosis. It may be recognized, however, that the choice of dyslipidemic patients is likely to affect outcome in this regard. This brings us to an important issue. As indicated in this review, several lines of evidence suggest that the scope of CETP inhibition for reducing atherosclerosis may be limited by the metabolic setting, in which gender, obesity, alcohol use, smoking, and triacylglycerol levels play important roles. Regarding the latter, we already indicated that CETP in animals can have antiatherogenic effects under hypertriacylglycerolemic conditions. This is of note when considering that a large fraction of patients who need intervention to prevent CAD exhibit hypertriacylglycerolemia, which clearly underscores the need to study the effects CETP inhibition under hypertriacylglycerolemic conditions. Another question that needs answering is whether CETP inhibition in (dyslipidemic) patients with either low or high CETP activity levels in plasma will have similar effects, an issue not addressed to date. Finally, the role of HDL in human metabolism exceeds that of mediating RCT. The effects of CETP inhibition on inflammation, thrombosis, endothelial function, and oxidative modification of proteins and lipids also warrant intensive study.
      Given that CETP is central to cholesterol and triacylglycerol transport in the circulation, a process that clearly differs in various dyslipidemias, and that CETP simultaneously affects the concentration and composition of both antiatherogenic and atherogenic lipoproteins, there is a need to sort out under what conditions how much CETP inhibition will render the desired effects. Future studies will have to clarify whether CETP inhibition improves vascular function and reduces atherosclerosis, and patience will be needed for proof of actual reduction in morbidity and mortality. Nonetheless, if a CETP inhibition-related increase in HDL-c proves to mediate vascular protection, CETP inhibitors (as sole treatment or in combination with other lipid-lowering drugs) will help refine the treatment of dyslipidemia in preventing cardiovascular disease.

      Acknowledgments

      J.A.K. is a Dr. Dekker Research fellow of the Netherlands Heart Foundation (1998T011). J.J.P.K. is an Established Investigator of The Netherlands Heart Foundation (2000T039).

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