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• W2788642078 abstract "Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized. Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized. Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is present in the plasma of humans, nonhuman primates, rabbits, and hamsters, but not in most other animal species (1.Ha 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 is a 74 kDa member of the lipid transfer protein/lipopolysaccharide binding protein (LTP/LBP) gene family (2.Beamer L.J. Carroll S.F. Eisenberg D. Crystal structure of human BPI and two bound phospholipids at 2.4 angstrom resolution.Science. 1997; 276: 1861-1864Crossref PubMed Google Scholar). CETP mediates bidirectional transfers (and thus an equilibration) of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoprotein particles (3.Barter 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 (138) Google Scholar). Because most of the CE originates in the HDL fraction in a reaction catalyzed by the enzyme, LCAT, and most of the TG enters plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs (Fig. 1). Activity of CETP also results in a net mass transfer of TG from VLDLs to LDLs and HDLs (Fig. 1). Inhibition of CETP activity reduces these lipid transfers and thus increases the concentration of HDL CE and decreases the concentration of CE in VLDLs and LDLs. The concentration of HDL-cholesterol (HDL-C) is a negative risk factor for atherosclerotic CVD (ASCVD), while the concentration of cholesterol in the non-HDL fractions is a positive risk factor. As humans that are CETP deficient have high plasma HDL-C levels and decreased non-HDL-C levels and are reported to be at decreased risk of developing ASCVD, it follows that inhibiting the activity of CETP may translate into a reduction in cardiovascular risk. Several approaches that inhibit CETP activity and increase plasma HDL-C levels have been proposed and tested. However, as inhibition of CETP activity also decreases apoB and non-HDL-C levels, any reduction in ASCVD risk that is mediated by these agents cannot be attributed to an increase in HDL-C levels alone. Approaches for inhibiting CETP include anti-CETP neutralizing antibodies (4.Hesler C.B. Tall A.R. Swenson T.L. Weech P.K. Marcel Y.L. Milne R.W. Monoclonal antibodies to the Mr 74,000 cholesteryl ester transfer protein neutralize all of the cholesteryl ester and triglyceride transfer activities in human plasma.J. Biol. Chem. 1988; 263: 5020-5023Abstract Full Text PDF PubMed Google Scholar, 5.Swenson T.L. Hesler C.B. Brown M.L. Quinet E. Trotta P.P. Haslanger M.F. Gaeta F.C. Marcel Y.L. Milne R.W. Tall A.R. Mechanism of cholesteryl ester transfer protein inhibition by a neutralizing monoclonal antibody and mapping of the monoclonal antibody epitope.J. Biol. Chem. 1989; 264: 14318-14326Abstract Full Text PDF PubMed Google Scholar, 6.Yen F.T. Deckelbaum R.J. Mann C.J. Marcel Y.L. Milne R.W. Tall A.R. Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody. Effects on cholesteryl ester formation and neutral lipid mass transfer in human plasma.J. Clin. Invest. 1989; 83: 2018-2024Crossref PubMed Google Scholar, 7.Fukasawa M. Arai H. Inoue K. Establishment of anti-human cholesteryl ester transfer protein monoclonal antibodies and radioimmunoassaying of the level of cholesteryl ester transfer protein in human plasma.J. Biochem. 1992; 111: 696-698Crossref PubMed Google Scholar, 8.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.J. Clin. Invest. 1989; 84: 129-137Crossref PubMed Google Scholar), antisense CETP oligonucleotides (9.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.J. Biol. Chem. 1998; 273: 5033-5036Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar), and an anti-CETP vaccine (10.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. 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 (282) Google Scholar, 11.Davidson M.H. Maki K. Umporowicz D. Wheeler A. Rittershaus C. Ryan U. The safety and immunogenicity of a CETP vaccine in healthy adults.Atherosclerosis. 2003; 169: 113-120Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). The anti-CETP vaccine reduced atherosclerosis in the New Zealand White rabbits (10.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. 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 (282) Google Scholar) and was effective in a phase I clinical trial in humans (11.Davidson M.H. Maki K. Umporowicz D. Wheeler A. Rittershaus C. Ryan U. The safety and immunogenicity of a CETP vaccine in healthy adults.Atherosclerosis. 2003; 169: 113-120Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar), but has not proceeded to clinical development. The neutralizing antibodies and the antisense oligonucleotide also did not proceed to clinical development. Several small molecule CETP inhibitors that reduce atherosclerosis in animal models extremely effectively have also been developed (12.Morehouse 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 (136) Google Scholar, 13.Okamoto 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 (491) Google Scholar). Four of these inhibitors (torcetrapib, dalcetrapib, evacetrapib, and anacetrapib) have been evaluated in large-scale randomized cardiovascular clinical outcome trials. While the trials with torcetrapib, dalcetrapib, and evacetrapib failed to show any cardiovascular benefit of CETP inhibition, treatment with anacetrapib significantly decreased major coronary events (14.Bowman L. Hopewell J.C. Chen F. Wallendszus K. Stevens W. Collins R. Wiviott S.D. Cannon C.P. Braunwald E. et al.Effects of anacetrapib in patients with atherosclerotic vascular disease.N. Engl. J. Med. 2017; 377: 1217-1227Crossref PubMed Scopus (417) Google Scholar). However, as the manufacturers of anacetrapib recently decided to suspend development of the drug, the future of CETP inhibition as a potential therapeutic option for reducing major cardiovascular events is currently uncertain. This review is concerned with the structure, function, and regulation of CETP and its inhibitors. It also outlines functions of CETP that are distinct from its lipid transfer activities, summarizes preclinical studies of CETP inhibition in animal models, and presents details of the outcomes of the randomized clinical outcome trials of the aforementioned small molecule CETP inhibitors. The structure of CETP has been the focus of numerous investigations. The LTP/LBP gene family, of which CETP is a member, includes several proteins, such as LBP, bactericidal permeability-increasing protein (BPI), and phospholipid transfer protein (PLTP), all of which have a high degree of structural similarity (15.Bingle C.D. Craven C.J. Meet the relatives: a family of BPI- and LBP-related proteins.Trends Immunol. 2004; 25: 53-55Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Early structural models of CETP that were based on the crystal structure of BPI (2.Beamer L.J. Carroll S.F. Eisenberg D. Crystal structure of human BPI and two bound phospholipids at 2.4 angstrom resolution.Science. 1997; 276: 1861-1864Crossref PubMed Google Scholar) identified CETP as a boomerang-shaped molecule with a hydrophobic lipid binding pocket at each end of the concave side (16.Guyard-Dangremont V. Tenekjian V. Chauhan V. Walter S. Roy P. Rassart E. Milne A.R. Immunochemical evidence that cholesteryl ester transfer protein and bactericidal/permeability-increasing protein share a similar tertiary structure.Protein Sci. 1999; 8: 2392-2398Crossref PubMed Scopus (10) Google Scholar, 17.Bruce C. Beamer L.J. Tall A.R. The implications of the structure of the bactericidal/permeability-increasing protein on the lipid-transfer function of the cholesteryl ester transfer protein.Curr. Opin. Struct. Biol. 1998; 8: 426-434Crossref PubMed Scopus (76) Google Scholar). CETP is a highly flexible molecule that undergoes a twisting motion when it binds to neutral lipids. This rotating motion enables CETP to bind to the surface of lipoproteins that vary widely in size and surface curvature and is a very important aspect of its mechanism of action. The assumption of a “boomerang” structure for CETP was confirmed by Qiu et al. (18.Qiu 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 (192) Google Scholar) who reported the first crystal structure of CETP at 3.5 Å resolution. That study identified the presence of a continuous central tunnel within the CETP molecule, which is unique among members of the LTP/LBP gene family. Two lipid binding pockets in the N- and C-terminal domains, and an amphipathic helix, helix X, located in the C-terminal domain of CETP have also been reported (18.Qiu 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 (192) Google Scholar, 19.Chirasani V.R. Revanasiddappa P.D. Senapati S. Structural plasticity of cholesteryl ester transfer protein assists the lipid transfer activity.J. Biol. Chem. 2016; 291: 19462-19473Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The central CETP tunnel can accommodate two CE molecules, one CE and one TG molecule, or two TG molecules (18.Qiu 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 (192) Google Scholar). These structural features of CETP have been confirmed in atomistic and coarse-grained simulation studies (20.Koivuniemi A. Vuorela T. Kovanen P.T. Vattulainen I. Hyvonen M.T. Lipid exchange mechanism of the cholesteryl ester transfer protein clarified by atomistic and coarse-grained simulations.PLOS Comput. Biol. 2012; 8: e1002299Crossref PubMed Scopus (42) Google Scholar), and by cryo-electron microscopy (21.Zhang 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 (92) Google Scholar). Evidence that structural integrity of the central CETP tunnel is essential for the transfer activity of CETP was established by mutating selected polar amino acid residues that are located in the tunnel into hydrophobic residues. This altered the tunnel architecture and reduced the transfer activity of CETP (18.Qiu 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 (192) Google Scholar). CETP transfers CE and TG between different lipoproteins by two mechanisms (Fig. 2). The first mechanism is a “shuttle” process (Fig. 2A) that involves random collisions of CETP with HDLs, LDLs, and VLDLs. This leads to the formation of complexes that facilitate bidirectional exchanges of CE and TG between each of the lipoproteins and CETP. The complexes subsequently dissociate from the lipoproteins where they were generated, and remain in the circulation until they randomly collide with another lipoprotein and participate in a further round of CE and TG exchanges. This process is repeated multiple times (3.Barter 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 (138) Google Scholar, 4.Hesler C.B. Tall A.R. Swenson T.L. Weech P.K. Marcel Y.L. Milne R.W. Monoclonal antibodies to the Mr 74,000 cholesteryl ester transfer protein neutralize all of the cholesteryl ester and triglyceride transfer activities in human plasma.J. Biol. Chem. 1988; 263: 5020-5023Abstract Full Text PDF PubMed Google Scholar). The crystal structure of CETP supports the shuttle mechanism and is consistent with the interaction of CETP with only one lipoprotein particle at a time (18.Qiu 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 (192) Google Scholar). The second mechanism of action of CETP involves the formation of a bridge between CETP and two lipoprotein particles to form a ternary complex (Fig. 2B) (21.Zhang 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 (92) Google Scholar, 22.Ihm 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). Neutral lipids move in both directions between the two lipoproteins through the tunnel in CETP. Evidence consistent with ternary complex formation comes from cryo-electron microscopy studies with anti-CETP polyclonal antibodies and atomistic molecular dynamics simulations (21.Zhang 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 (92) Google Scholar). The results of these studies support the penetration of the N-terminal domain of CETP into the surface of an HDL particle together with a concomitant interaction of the C-terminal domain of CETP with an LDL or VLDL particle. Additional analyses have indicated that the transfer of CEs between HDLs and LDLs, or HDLs and VLDLs, by this mechanism is dependent on conformational changes in the N- and the C-terminal domains of CETP that increase tunnel continuity and improve neutral lipid accessibility (19.Chirasani V.R. Revanasiddappa P.D. Senapati S. Structural plasticity of cholesteryl ester transfer protein assists the lipid transfer activity.J. Biol. Chem. 2016; 291: 19462-19473Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21.Zhang 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 (92) Google Scholar). However, it should be noted that these observations are not supported by other electron microscopy studies in which HDLs were shown to bind to the N- as well as the C-terminal domain of CETP (23.Lauer M.E. Graff-Meyer A. Rufer A.C. Maugeais C. von der Mark E. Matile H. D'Arcy B. Magg C. Ringler P. Muller S.A. et al.Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP.J. Struct. Biol. 2016; 194: 191-198Crossref PubMed Scopus (18) Google Scholar). It should be noted, however, that no interactions of CETP with LDLs, or formation of HDL-CETP-LDL complexes, were observed in that study, and that monoclonal antibodies targeted toward the N- and C-terminal domains of CETP did not prevent the penetration of CETP into the HDL surface or affect CETP activity (23.Lauer M.E. Graff-Meyer A. Rufer A.C. Maugeais C. von der Mark E. Matile H. D'Arcy B. Magg C. Ringler P. Muller S.A. et al.Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP.J. Struct. Biol. 2016; 194: 191-198Crossref PubMed Scopus (18) Google Scholar). When taken together, these findings do not support the formation of a ternary complex as a major mechanism of action of CETP. There are, by contrast, multiple reports of anti-CETP antibodies inhibiting CETP-mediated transfers of CE and TG between HDLs and other lipoproteins (5.Swenson T.L. Hesler C.B. Brown M.L. Quinet E. Trotta P.P. Haslanger M.F. Gaeta F.C. Marcel Y.L. Milne R.W. Tall A.R. Mechanism of cholesteryl ester transfer protein inhibition by a neutralizing monoclonal antibody and mapping of the monoclonal antibody epitope.J. Biol. Chem. 1989; 264: 14318-14326Abstract Full Text PDF PubMed Google Scholar, 24.Wang S. Deng L. Milne R.W. Tall A.R. Identification of a sequence within the C-terminal 26 amino acids of cholesteryl ester transfer protein responsible for binding a neutralizing monoclonal antibody and necessary for neutral lipid transfer activity.J. Biol. Chem. 1992; 267: 17487-17490Abstract Full Text PDF PubMed Google Scholar). These discrepant findings highlight a potential dependency of CETP-mediated neutral lipid transfers on the antibodies that are used to target the N- and C-terminal domains of the CETP molecule. For example, Zhang et al. (21.Zhang 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 (92) Google Scholar) used polyclonal antibodies that recognized a large area of the CETP molecule, whereas the more recent studies of Lauer et al. (23.Lauer M.E. Graff-Meyer A. Rufer A.C. Maugeais C. von der Mark E. Matile H. D'Arcy B. Magg C. Ringler P. Muller S.A. et al.Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP.J. Struct. Biol. 2016; 194: 191-198Crossref PubMed Scopus (18) Google Scholar) were undertaken with monoclonal antibodies that recognize specific epitopes within the protein. Transcription of the CETP gene is under the control of extrinsic and intrinsic factors. For example, dietary cholesterol upregulates CETP expression in mice transgenic for human CETP (25.Masucci-Magoulas L. Plump A. Jiang X.C. Walsh A. Breslow J.L. Tall A.R. Profound induction of hepatic cholesteryl ester transfer protein transgene expression in apolipoprotein E and low density lipoprotein receptor gene knockout mice. A novel mechanism signals changes in plasma cholesterol levels.J. Clin. Invest. 1996; 97: 154-161Crossref PubMed Google Scholar, 26.Quinet E.M. Agellon L.B. Kroon P.A. Marcel Y.L. Lee Y.C. Whitlock M.E. Tall A.R. Atherogenic diet increases cholesteryl ester transfer protein messenger RNA levels in rabbit liver.J. Clin. Invest. 1990; 85: 357-363Crossref PubMed Google Scholar, 27.Jiang X.C. Agellon L.B. Walsh A. Breslow J.L. Tall A. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.J. Clin. Invest. 1992; 90: 1290-1295Crossref PubMed Google Scholar). Plasma cholesterol levels also correlate with CETP mass in human plasma (28.Martin L.J. Connelly P.W. Nancoo D. Wood N. Zhang Z.J. Maguire G. Quinet E. Tall A.R. Marcel Y.L. McPherson R. Cholesteryl ester transfer protein and high density lipoprotein responses to cholesterol feeding in men: relationship to apolipoprotein E genotype.J. Lipid Res. 1993; 34: 437-446Abstract Full Text PDF PubMed Google Scholar). Studies of transgenic mice have established that induction of human CETP gene expression in response to cholesterol is a consequence of transactivation of a nuclear receptor binding site in the promoter region of the gene by the transcription factors, liver X receptor (LXR) and retinoid X receptor (29.Luo Y. Tall A.R. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element.J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Google Scholar, 30.Gautier T. de Haan W. Grober J. Ye D. Bahr M.J. Claudel T. Nijstad N. Van Berkel T.J. Havekes L.M. Manns M.P. et al.Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice.J. Lipid Res. 2013; 54: 2195-2205Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). These results are supported by studies of LXR agonists that increase CETP expression in mice transgenic for human CETP, and in mice with LXRα deficiency in which CETP expression is not increased by administration of an LXR agonist (31.Honzumi S. Shima A. Hiroshima A. Koieyama T. Ubukata N. Terasaka N. LXRalpha regulates human CETP expression in vitro and in transgenic mice.Atherosclerosis. 2010; 212: 139-145Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). The human CETP gene is also regulated by SREBP-1, a transcription factor that transactivates sterol regulatory-like elements in the promoter region of the gene (32.Chouinard Jr., R.A. Luo Y. Osborne T.F. Walsh A. Tall A.R. Sterol regulatory element binding protein-1 activates the cholesteryl ester transfer protein gene in vivo but is not required for sterol up-regulation of gene expression.J. Biol. Chem. 1998; 273: 22409-22414Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Light to moderate, but not heavy, alcohol consumption is generally considered to decrease CETP mass and activity, increase HDL-C levels, and decrease CVD risk. However, investigations into this relationship have produced conflicting results. Some investigators have confirmed the association (33.Hannuksela M.L. Liinamaa M.J. Kesaniemi Y.A. Savolainen M.J. Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers.Atherosclerosis. 1994; 110: 35-44Abstract Full Text PDF PubMed Scopus (128) Google Scholar), while others have found that the alcohol-mediated increase in HDL-C levels is independent of CETP activity (34.Riemens S.C. van Tol A. Hoogenberg K. van Gent T. Scheek L.M. Sluiter W.J. Dullaart R.P. Higher high density lipoprotein cholesterol associated with moderate alcohol consumption is not related to altered plasma lecithin:cholesterol acy­ltransferase and lipid transfer protein activity levels.Clin. Chim. Acta. 1997; 258: 105-115Crossref PubMed Scopus (0) Google Scholar, 35.Ito T. Nishiwaki M. Ishikawa T. Nakamura H. CETP and LCAT activities are unrelated to smoking and moderate alcohol consumption in healthy normolipidemic men.Jpn. Circ. J. 1995; 59: 541-546Crossref PubMed Google Scholar) and unrelated to effects on genes that regulate HDL levels (36.Marques-Vidal P. Bochud M. Paccaud F. Waterworth D. Bergmann S. Preisig M. Waeber G. Vollenweider P. No interaction between alcohol consumption and HDL-related genes on HDL cholesterol levels.Atherosclerosis. 2010; 211: 551-557Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Physical activity in the form of endurance exercise also increases HDL-C levels, decreases plasma CETP levels, and reduces CVD risk in humans (37.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.Arterioscler. Thromb. 1993; 13: 1359-1367Crossref PubMed Google Scholar). However, aerobic exercise has been reported not to affect CETP activity in mice transgenic for the human CETP gene (38.Rocco D.D. Okuda L.S. Pinto R.S. Ferreira F.D. Kubo S.K. Nakandakare E.R. Quintao E.C. Catanozi S. Passarelli M. Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice.Lipids. 2011; 46: 617-625Crossref PubMed Scopus (16) Google Scholar) or plasma CETP levels in humans (39.Tiainen S. Luoto R. Ahotupa M. Raitanen J. Vasankari T. 6-mo aerobic exercise intervention enhances the lipid peroxide transport function of HDL.Free Radic. Res. 2016; 50: 1279-1285Crossref PubMed Scopus (8) Google Scholar, 40.Brites F. Verona J. De Geitere C. Fruchart J.C. Castro G. Wikinski R. Enhanced cholesterol efflux promotion in well-trained soccer players.Metabolism. 2004; 53: 1262-1267Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). The first report of a loss-of-function mutation in the CETP gene was in a Japanese population with a G-to-A substitution in the 5′-splice donor site of intron 14 (Int 14A) (41.Brown 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 Google Scholar). Homozygosity for this mutation is associated with very low or undetectable CETP activity, markedly elevated plasma HDL-C, apoA-I, and apoE levels, a moderate reduction in VLDL-cholesterol, LDL-cholesterol (LDL-C), and apoB levels, a low incidence of atherosclerosis, and increased life span compared with unaffected family members (41.Brown 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 Google Scholar, 42.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.N. Engl. J. Med. 1990; 323: 1234-1238Crossref PubMed Google Scholar). HDLs isolated from people homozygous for this mutation, as well as compound heterozygotes, also have HDLs that are larger than the HDLs in unaffected individuals (41.Brown 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.N" @default.
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• W2788642078 date "2018-01-01" @default.
• W2788642078 modified "2023-10-03" @default.
• W2788642078 title "Cholesteryl ester transfer protein and its inhibitors" @default.
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