Novel mutations of CETP gene in Italian subjects with hyeralphalipoproteinemia

High-density lipoproteins (HDLs) are considered anti-atherogenic because they mediate peripheral cell cholesterol transport to the liver for excretion and degradation. An important step in this reverse cholesterol-transport pathway is the uptake of cellular cholesterol by a specific subclass of small, lipid-poor apolipoprotein A-I particles designated preβ-HDL. The two lipid-transfer proteins present in human plasma, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), have both been implicated in the formation of preβ-HDL. In order to investigate the relative contribution of each of these proteins, we used transgenic mouse models. Comparisons were made between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice (huPLTPtg) and mice transgenic for both lipid-transfer proteins (huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP activity, PLTP activity or both activities, respectively. We evaluated the generation of preβ-HDL in mouse plasma by immunoblotting and crossed immuno-electrophoresis. Generation of preβ-HDL was equal in huCETPtg and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice, preβ-HDL generation was 3-fold higher than in plasma from either wild-type or huCETPtg mice. Our findings demonstrate that, of the two plasma lipid-transfer proteins, PLTP rather than CETP is responsible for the generation of preβ-HDL. These data support the hypothesis of a role for PLTP in the initial stage of reverse cholesterol transport.

Phospholipid transfer protein

Cholesterylester transfer protein

Reverse cholesterol transport

Cholesteryl ester

10.1042/0264-6021:3600379

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The role of plasma phospholipid transfer protein (PLTP) in the development of atherosclerosis : studies in genetically modified mice

Jessica Lie

Complications of atherosclerosis are the principal cause of mortality in Western societies. Epidemiological studies have shown that a high HDL cholesterol level in plasma is inversely correlated with the risk for atherosclerosis. The exact biological mechanism behind this finding is not known. There are many factors that affect HDL metabolism. In vitro and in vivo studies demonstrated that plasma phospholipid transfer protein (PLTP) plays a major role in phospholipid transfer processes between lipoproteins, and also in modulating size and composition of HDL particles. The aim of this thesis was to clarify the role of PLTP in HDL metabolism and in the development of atherosclerosis. Normal mice lack cholesteryl ester transfer protein (CETP) and have very low LDL plasma levels compared with humans. Therefore we used a genetically modified mouse model with a humanlike lipoprotein profile. These animals are transgenic for CETP and carry one mutated allele of the LDL receptor (huCETPtg/LDL-R+I-).

Phospholipid transfer protein

Cholesterylester transfer protein

Reverse cholesterol transport

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The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis

Journal of Lipid Research (2008)

David Masson Xian‐Cheng Jiang Laurent Lagrost Alan R. Tall

The plasma lipid transfer proteins promote the exchange of neutral lipids and phospholipids between the plasma lipoproteins. Cholesteryl ester transfer protein (CETP) facilitates the removal of cholesteryl esters from HDL and thus reduces HDL levels, while phospholipid transfer protein (PLTP) promotes the transfer of phospholipids from triglyceride-rich lipoproteins into HDL and increases HDL levels. Studies in transgenic mouse models and in humans with rare genetic deficiencies (CETP) or common genetic variants (CETP and PLTP) highlight the central role of these molecules in regulating HDL levels. Human CETP deficiency is associated with dramatic elevations of HDL cholesterol and apolipoprotein A-I levels, while PLTP variants with increased expression are associated with higher HDL levels. A recent meta-analysis suggests that common CETP alleles causing reduced CETP and increased HDL levels are associated with reduced coronary heart disease. The failure of a clinical trial with the CETP inhibitor torcetrapib may have been related in part to off-target toxicity. Ongoing phase 3 clinical trials with other CETP inhibitors may help to clarify if this strategy can ultimately be successful in the treatment of atherosclerosis. The plasma lipid transfer proteins promote the exchange of neutral lipids and phospholipids between the plasma lipoproteins. Cholesteryl ester transfer protein (CETP) facilitates the removal of cholesteryl esters from HDL and thus reduces HDL levels, while phospholipid transfer protein (PLTP) promotes the transfer of phospholipids from triglyceride-rich lipoproteins into HDL and increases HDL levels. Studies in transgenic mouse models and in humans with rare genetic deficiencies (CETP) or common genetic variants (CETP and PLTP) highlight the central role of these molecules in regulating HDL levels. Human CETP deficiency is associated with dramatic elevations of HDL cholesterol and apolipoprotein A-I levels, while PLTP variants with increased expression are associated with higher HDL levels. A recent meta-analysis suggests that common CETP alleles causing reduced CETP and increased HDL levels are associated with reduced coronary heart disease. The failure of a clinical trial with the CETP inhibitor torcetrapib may have been related in part to off-target toxicity. Ongoing phase 3 clinical trials with other CETP inhibitors may help to clarify if this strategy can ultimately be successful in the treatment of atherosclerosis. CHOLESTERYL ESTER TRANSFER PROTEINDiscovery and characterization of CETPMore than 40 years ago in this journal, Nichols and Smith (1Nichols A.V. Smith L. Effect of very low-density lipoproteins on lipid transfer in incubated serum.J. Lipid Res. 1965; 6: 206-210Abstract Full Text PDF PubMed Google Scholar) described a factor in human plasma that was able to stimulate the reciprocal exchange of triglycerides and cholesteryl esters between lipoprotein subclasses. The first biochemical characterization of a plasma lipid transfer protein came 13 years later (2Pattnaik N.M. Montes A. Hughes L.B. Zilversmit D.B. Cholesteryl ester exchange protein in human plasma isolation and characterization.Biochim. Biophys. Acta. 1978; 530: 428-438Crossref PubMed Scopus (188) Google Scholar). Complete purification of cholesteryl ester transfer protein (CETP) (3Hesler C.B. Swenson T.L. Tall A.R. Purification and characterization of a human plasma cholesteryl ester transfer protein.J. Biol. Chem. 1987; 262: 2275-2282Abstract Full Text PDF PubMed Google Scholar) and the subsequent cloning of the CETP cDNA (4Drayna D. Jarnagin A.S. McLean J. Henzel W. Kohr W. Fielding C. Lawn R. Cloning and sequencing of human cholesteryl ester transfer protein cDNA.Nature. 1987; 327: 632-634Crossref PubMed Scopus (300) Google Scholar) were achieved in 1987. These studies indicated that mature CETP is a 476 amino acid protein (74 kDa) with a highly hydrophobic amino acid content and four N-linked glycosylation sites. Neutralizing CETP monoclonal antibodies showed that this molecule was responsible for all cholesteryl ester (CE) and triglyceride (TG) transfer activity in human plasma and that inhibition of activity in rabbits resulted in increased HDL levels and a reduced content of CE in VLDL (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar). Shortly thereafter, the elucidation of human genetic deficiency of CETP established the key role of this molecule in human lipoprotein metabolism (6Brown 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. al et Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins.Nature. 1989; 342: 448-451Crossref PubMed Scopus (407) Google Scholar). Recently, the crystal structure of CETP revealed an elongated boomerang shaped molecule with the curvature of the concave surface likely fitting to the convex curvature of the lipoprotein surface (7Qiu 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. al et 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 (210) Google Scholar) (Fig. 1). A unique 60 å long hydrophobic tunnel with two distinct openings traverses the core of the protein. This tunnel can be filled with two CE molecules and plugged by two phospholipid molecules at each end. It has been proposed that upon CETP binding at the lipoprotein surface, phospholipids bound at the mouth of the tunnel merge into the phospholipid monolayer and allow neutral lipids to enter and exit the tunnel. A C-terminal amphipathic helix (Fig. 1, black arrow) recognized by the neutralizing CETP monoclonal antibody (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar) is situated at the mouth of the N-terminal entrance to the lipid binding tunnel and may play a role in facilitating entry of neutral lipid into CETP. The CETP structure is consistent with the earlier findings that CETP binds neutral lipids and shuttles them between plasma lipoproteins in a carrier-mediated mechanism (8Barter P.J. Jones M.E. Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins.J. Lipid Res. 1980; 21: 238-249Abstract Full Text PDF PubMed Google Scholar).Role of CETP in lipoprotein metabolismIn humans and monkeys, CETP is expressed in liver (parenchymal and nonparenchymal cells), small intestine (enterocytes), adipose tissue, and spleen (4Drayna D. Jarnagin A.S. McLean J. Henzel W. Kohr W. Fielding C. Lawn R. Cloning and sequencing of human cholesteryl ester transfer protein cDNA.Nature. 1987; 327: 632-634Crossref PubMed Scopus (300) Google Scholar). There is also significant expression of CETP in macrophages, and bone marrow transplantation experiments using as donors mice expressing the human CETP transgene under the control of its natural promoter suggest that macrophages make a significant contribution to plasma CETP levels (9Van Eck M. Ye D. Hildebrand R.B. Kruijt J.Kar Haan W.de Hoekstra M. Rensen P.C. Ehnholm C. Jauhiainen M. Berkel T.J. Van Important role for bone marrow-derived cholesteryl ester transfer protein in lipoprotein cholesterol redistribution and atherosclerotic lesion development in LDL receptor knockout mice.Circ. Res. 2007; 100: 678-685Crossref PubMed Scopus (39) Google Scholar). CETP gene expression is stimulated by dietary cholesterol and endogenous hypercholesterolemia as a result of activation of liver X receptor/retinoid X receptor transcription factors bound to the proximal promoter of the human CETP gene (10Luo 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 Scopus (304) Google Scholar). In human plasma, CETP is present at concentrations of ∼2 μg/mL, with moderately higher levels in dyslipidemic subjects, and is mainly associated with high density lipoproteins (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar). Plasma CE transfer activity is dependent on both CETP concentration and the ability of CETP to interact with lipoproteins. This interaction can be stimulated by free fatty acids generated during hydrolysis of dietary TGs (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar) or inhibited by specific apolipoproteins such as apoC-I or apoF (11Wang X. Driscoll D.M. Morton R.E. Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F.J. Biol. Chem. 1999; 274: 1814-1820Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 12Gautier T. Masson D. Barros J.P. de Athias A. Gambert P. Aunis D. Lagrost M.H. Metz-Boutigue, and L. Human apolipoprotein CI accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity.J. Biol. Chem. 2000; 275: 37504-37509Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). Due to the mechanism of lipid transfer, CETP can only promote the net mass transfer of lipids between lipoprotein subclasses that have different CE/TG ratios. Therefore, CETP facilitates the transfer of CEs from CE-rich LDL and HDL toward VLDL. CETP promotes the reciprocal enrichment of LDL and HDL with TGs derived from VLDL (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar). Unlike CEs, TGs can be hydrolyzed in the plasma compartment through the action of lipases. Subsequent hydrolysis of TG in LDL promotes their remodeling with the generation of small dense LDL with a smaller neutral lipid core. A similar mechanism also occurs in HDL, and hydrolysis of large-triglyceride-enriched HDL generates smaller HDL3 together with the release of lipid poor apolipoprotein A-I (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar).ROLE OF CETP IN ATHEROSCLEROSISPredictions from lipoprotein physiologyBy transferring CEs from HDL toward apoB-containing lipoproteins, CETP decreases the concentration of HDL cholesterol and apoA-I and increases the concentration of CE in VLDL and remnants. In addition, CETP activity raises levels of LDL cholesterol and apo B, most likely due to downregulation of hepatic LDL receptors (5Tall A. Plasma lipid transfer proteins.Annu. Rev. Biochem. 1995; 64: 235-257Crossref PubMed Scopus (271) Google Scholar). Small, dense LDLs generated by CETP and lipases may be particularly atherogenic because of increased affinity for artery wall proteoglycans and increased susceptibility to oxidation. In contrast with these pro-atherogenic effects, the remodeling of HDL particles by CETP is accompanied by the release of lipid-poor apoA-I, which is the preferential acceptor for ABCA1-mediated cholesterol efflux from macrophage foam cells. However, this effect may be offset by a decrease in large HDL particles that promote cholesterol efflux in part via the ABCG1 pathway (13Matsuura F. Wang N. Chen W. Jiang X.C. Tall A.R. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway.J. Clin. Invest. 2006; 116: 1435-1442Crossref PubMed Scopus (257) Google Scholar). In the steady state, CETP activity appears not to change the overall efficiency of reverse cholesterol transport, though the lipoproteins mediating reverse cholesterol transport are likely different (i.e., primarily remnants and LDL in the presence of CETP activity and HDL in CETP deficiency). Any beneficial effect of CETP inhibition likely accrues from decreased cholesterol uptake and increased cholesterol efflux in macrophage foam cells and in vascular cells of atherosclerotic plaques (14Tall A.R. Terasaka L.Yvan-Charvet, N. Pagler T. Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.Cell Metab. 2008; 7: 365-375Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar).Animal studiesInterestingly, CETP is not present in all animal species. Introduction of the human CETP gene in transgenic mouse models has led to varied effects on atherosclerosis. CETP expression increased atherosclerosis in hypercholesterolemic mouse models, such as apoE and LDL-receptor-deficient mice (15Marotti K.R. Castle C.K. Boyle T.P. Lin A.H. Murray R.W. Melchior G.W. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein.Nature. 1993; 364: 73-75Crossref PubMed Scopus (410) Google Scholar, 16Plump A.S. Bruce L.Masucci-Magoulas, 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.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1105-1110Crossref PubMed Scopus (201) Google Scholar), and in a mouse model of mixed hyperlipidemia expressing apoE(Leiden) (17Westerterp M. Hoogt C.C. van der Haan W.de Offerman E.H. Jukema G.M. Dallinga-Thie, J.W. Havekes L.M. Rensen P.C. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2552-2559Crossref PubMed Scopus (170) Google Scholar). By contrast, in hypertriglyceridemic apoCIII Tg mice, expression of CETP can be either non- or anti-atherogenic (18Hayek T. Jiang L.Masucci-Magoulas, X. Walsh A. Rubin E. Breslow J.L. Tall A.R. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.J. Clin. Invest. 1995; 96: 2071-2074Crossref PubMed Scopus (250) Google Scholar). In mice, CETP activity appears to be pro-atherogenic when it causes both reduced HDL levels and increased levels of CE in remnants and LDL, while it is nonatherogenic in a setting of hypertriglyceridemia and prominent accumulation of small lipid-poor, apoA-I-rich HDL particles.HUMAN STUDIESGenetic CETP deficiencyGenetic CETP deficiency was discovered in Japanese families with increased HDL levels (6Brown 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. al et Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins.Nature. 1989; 342: 448-451Crossref PubMed Scopus (407) Google Scholar, 19Inazu 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 Scopus (697) Google Scholar). Homozygous deficient subjects display dramatic increases in HDL-C (approximately + 100–200%) as well as decreases in LDL-C and apoB levels (approximately −40%). HDL from homozygous CETP-deficient subjects are very large and enriched in apoE and show an enhanced ability to promote cholesterol efflux from macrophages in part through the ABCG1 pathway (13Matsuura F. Wang N. Chen W. Jiang X.C. Tall A.R. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway.J. Clin. Invest. 2006; 116: 1435-1442Crossref PubMed Scopus (257) Google Scholar). LDL particles from CETP-deficient subjects are heterogeneous in size and display a reduced affinity for the LDL receptor. In a cross-sectional survey of Japanese/American men, heterozygotes for CETP gene defects had an increased risk for coronary heart disease (20Zhong 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.J. Clin. Invest. 1996; 97: 2917-2923Crossref PubMed Scopus (544) Google Scholar). However, this finding was not confirmed in a subsequent prospective study in the same population, in which a trend to a lower incidence of stroke and coronary heart disease (CHD) was apparent in men with heterozygous CETP deficiency (21Curb J.D. Abbott R.D. Rodriguez B.L. Masaki K. Chen R. Sharp D.S. Tall A.R. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly.J. Lipid Res. 2004; 45: 948-953Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar).CETP polymorphismsAlthough many studies have demonstrated associations between CETP single-nucleotide polymorphisms in Caucasian populations and small changes in plasma CETP and HDL concentration, the relationship between these polymorphisms and susceptibility to atherosclerotic cardiovascular disease has been inconsistent. A recent meta-analysis of three different single nucleotide polymorphisms (SNPs) in the CETP gene (two of them in linkage disequilbrium) in 113,833 subjects, including 27,196 cases of CHD, showed a significant or borderline significant reduction in CHD for the CETP alleles associated with lower CETP and higher HDL levels (22Thompson A. Angelantonio E.Di Sarwar N. Erqou S. Saleheen D. Dullaart R.P. Keavney B. Ye Z. Danesh J. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk.JAMA. 2008; 299: 2777-2788Crossref PubMed Scopus (421) Google Scholar) (Fig. 2A). The protective effect of HDL elevation associated with lower CETP levels was similar to that afforded by HDL elevation in prospective epidemiological studies. One caveat to the conclusions of this meta-analysis is that findings may have been influenced by publication bias. Recently, a genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol, including CETP TaqIB, was found to be an independent risk factor for incident cardiovascular disease, and in this analysis, HDL- and LDL-associated SNPs acted independently (23Kathiresan S. Melander O. Anevski D. Guiducci C. Burtt N.P. Roos C. Hirschhorn J.N. Berglund G. Hedblad B. Groop L. al et Polymorphisms associated with cholesterol and risk of cardiovascular events.N. Engl. J. Med. 2008; 358: 1240-1249Crossref PubMed Scopus (572) Google Scholar). Overall, the evidence linking HDL-associated SNPs with CHD is weaker than that for LDL, consistent with the idea that LDL is the cause of atherosclerosis, while HDL is a modifying factor. Notably, these studies show either no effect of CETP genetic variants on CHD or a protective effect, but there is no consistent relationship linking reduced CETP levels to increased CHD.Fig. 2Relationship of CETP with atherosclerosis. A: Observed per-allele odds ratios for coronary disease with CETP variants versus odds ratios derived from prospective studies of HDL-C levels. A significant reduction in CHD is observed for the CETP alleles associated with lower CETP and higher HDL levels. Interestingly, the protective effect of HDL elevation associated with lower CETP levels is similar to that afforded by HDL elevation in prospective epidemiological studies. B: The ILLUMINATE study was stopped prematurely as a result of an excess of deaths and cardiovascular disease in the group receiving torcetrapib. Potential adverse effects of torcetrapib include off-target effects, such as increases in blood pressure, sodium, bicarbonate, and aldosterone levels, as well as a decrease in potassium levels. However mechanism-related adverse effects cannot be ruled out. Beneficial effects would include increase in cholesterol efflux via ABCG1 resulting in decrease foam cell formation and a decrease coronary atherosclerosis. In the ILLUSTRATE study, there was an inverse relationship between change in HDL and change in percentage of atheroma volume in the group receiving torcetrapib.View Large Image Figure ViewerDownload Hi-res image Download (PPT)CETP inhibitorsAll CETP inhibition strategies have been effective at increasing HDL levels and decreasing atherosclerosis in rabbits (24Barter 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.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 160-167Crossref PubMed Scopus (702) Google Scholar). Clinical trials in humans using CETP inhibitors, such as torcetrapib, have shown marked increases in HDL and moderate reductions in LDL (25Brousseau 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.N. Engl. J. Med. 2004; 350: 1505-1515Crossref PubMed Scopus (705) Google Scholar). Unfortunately, a large phase 3 clinical trial called ILLUMINATE involving torcetrapib was stopped prematurely as a result of an excess of deaths and cardiovascular disease in the group receiving torcetrapib and atorvastatin compared with atorvastatin alone (26Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Mosca J.Lopez-Sendon, L. Tardif J.C. Waters D.D. al et Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2576) Google Scholar). The reasons for the adverse outcome are uncertain. Torcetrapib administration was associated with a number of undesirable off-target effects that could have contributed to increase mortality/morbidity (Fig. 2B). They included increases in blood pressure, sodium, bicarbonate, and aldosterone levels as well as a decrease in potassium levels (26Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Mosca J.Lopez-Sendon, L. Tardif J.C. Waters D.D. al et Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2576) Google Scholar). It seems that these adverse effects were molecule specific and not related to CETP inhibition (27Forrest M.J. Bloomfield D. Briscoe R.J. Brown P.N. Cumiskey A.M. Ehrhart J. Hershey J.C. Keller W.J. Ma X. McPherson H.E. al et Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.Br. J. Pharmacol. 2008; 154: 1465-1473Crossref PubMed Scopus (259) Google Scholar). The mechanism of hypertension appears to result in part from an increased production of adrenal steroids, including aldosterone and cortisol (27Forrest M.J. Bloomfield D. Briscoe R.J. Brown P.N. Cumiskey A.M. Ehrhart J. Hershey J.C. Keller W.J. Ma X. McPherson H.E. al et Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.Br. J. Pharmacol. 2008; 154: 1465-1473Crossref PubMed Scopus (259) Google Scholar). Post hoc analysis of the ILLUSTRATE study showed that while the majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis, a significant regression of coronary atherosclerosis was observed in patients in the highest HDL-C quartile. In this post hoc analysis, there was a continuous inverse relationship between HDL levels and the percentage of atheroma volume (28Nicholls S.J. Tuzcu E.M. Brennan D.M. Tardif J-C. Nissen S.E. CETP Inhibition, HDL Raising and Progression of Coronary Atherosclerosis: Insights from ILLUSTRATE.Circulation. 2008; 118: 2506-2514Crossref PubMed Scopus (187) Google Scholar). Moreover, this relationship was only clearly seen in the group receiving the CETP inhibitor, strongly suggesting that in patients achieving high HDL levels, HDL particles were functional in promoting regression of atherosclerosis.Two other CETP inhibitors, anacetrapib (Merck) and dalcetrapib (Roche), are in advanced clinical studies (29Krishna R. Anderson M.S. Bergman A.J. Jin B. Fallon M. Cote J. Rosko K. Lutz C.Chavez-Eng, R. Bloomfield D.M. al et Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.Lancet. 2007; 370: 1907-1914Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 30de 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.Circulation. 2002; 105: 2159-2165Crossref PubMed Scopus (452) Google Scholar). Unlike torcetrapib, these agents do not appear to cause hypertension. Dalcetrapib has a distinct mechanism of action compared with anacetrapib and torcetrapib and likely covalently modifies a Cys-H group in the N-terminal part of the lipid binding tunnel of CETP. Anacetrapib is a more potent CETP inhibitor than dalcetrapib and produces larger effects on HDL and LDL levels. Ongoing phase 3 clinical studies with various CETP inhibitors may help to determine if the addition of CETP inhibitors to statins can lead to a reduction in atherosclerotic cardiovascular disease.PHOSPHOLIPID TRANSFER PROTEINDiscovery and characterizationEarlier biochemical studies showed that a second lipid transfer protein distinct from CETP was present in human plasma (31Tall A.R. Abreu E. Shuman J. Separation of a plasma phospholipid transfer protein from cholesterol ester/phospholipid exchange protein.J. Biol. Chem. 1983; 258: 2174-2180Abstract Full Text PDF PubMed Google Scholar). This protein was unable to transfer neutral lipids between LDL and HDL, but unlike CETP promoted net mass transfer of phospholipids from phospholipid vesicles or lipolyzed VLDL particles into HDL (32Tall A.R. Krumholz S. Olivecrona T. Deckelbaum R.J. Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis.J. Lipid Res. 1985; 26: 842-851Abstract Full Text PDF PubMed Google Scholar). Cloning of the cDNA revealed that phospholipids transfer protein (PLTP) is a 476 amino acid protein (Mr 81 kDa) with six N-linked glycosylation sites (33Day J.R. Albers J.J. Gilbert C.E. Lofton-Day, T.L. Ching A.F. Grant F.J. Marcovina P.J. O'Hara, S.M. Adolphson J.L. Complete cDNA encoding human phospholipid transfer protein from human endothelial cells.J. Biol. Chem. 1994; 269: 9388-9391Abstract Full Text PDF PubMed Google Scholar). PLTP displays an ∼25% amino acid identity with CETP and with two other proteins, the lipopolysaccharide (LPS) binding protein and the bactericidal permeability increasing protein, involved in the defense of the organism against LPS from gram negative bacteria. The four proteins comprise the lipid transfer/LPS binding family. They also share significant homology with the PLUNC proteins that could be involved in the local innate immune response against bacteria in oral, nasal, and respiratory epithelia (34Bingle C.D. Craven C.J. PLUNC: a novel family of candidate host defence proteins expressed in the upper airways and nasopharynx.Hum. Mol. Genet. 2002; 11: 937-943Crossref PubMed Scopus (204) Google Scholar). Similar to CETP, PLTP probably acts as a carrier that shuttles phospholipids between lipoprotein particles. In addition to phospholipids, PLTP is able to transfer other amphipatic compounds, such as free cholesterol, LPS, and vitamin E (35Hailman E. Albers J.J. Wolfbauer G. Tu A.Y. Wright S.D. Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein.J. Biol. Chem. 1996; 271: 12172-12178Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 36Jiang X.C. Tall A.R. Qin S. Lin M. Schneider M. Lalanne F. Deckert V. Desrumaux C. Athias A. Witztum J.L. al et Phospholipid transfer protein deficiency protects circulating lipoproteins from oxidation due to the enhanced accumulation of vitamin E.J. Biol. Chem. 2002; 277: 31850-31856Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar).Role of PLTP in lipoprotein metabolismIn contrast with CETP, PLTP is widely expressed in organs and cells (33Day J.R. Albers J.J. Gilbert C.E. Lofton-Day, T.L. Ching A.F. Grant F.J. Marcovina P.J. O'Hara, S.M. Adolphson J.L. Complete cDNA encoding human phospholipid transfer protein from human endothelial cells.J. Biol. Chem. 1994; 269: 9388-9391Abstract Full Text PDF PubMed Google Scholar). High levels of PLTP mRNA are especially seen in the brain, the lung, and the gonads, suggesting specific functions of PLTP in these organs. PLTP gene expression is controlled by nuclear receptors such as farnesoid X receptor and liver X receptor (37Mak P.A. Anisfeld H.R. Kast-Woelbern, A.M. Edwards P.A. Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors.J. Lipid Res. 2002; 43: 2037-2041Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). In addition to promoting transfer of phospholipids from VLDL and chylomicrons into HDL (38Jiang X.C. Bruce C. Mar J. Lin M. Ji Y. Francone O.L. Tall A.R. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.J. Clin. Invest. 1999; 103: 907-914Crossref PubMed Scopus (319) Google Scholar), PLTP may contribute to the remodeling of HDL particles. In vitro studies suggest that when th

Cholesterylester transfer protein

Phospholipid transfer protein

Reverse cholesterol transport

High-density lipoprotein

10.1194/jlr.r800061-jlr200

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Citations (125)

Elevation of plasma phospholipid transfer protein in transgenic mice increases VLDL secretion

Journal of Lipid Research (2002)

Jessica Lie Rini de Crom Teus van Gent Rien van Haperen L.M. Scheek

Two lipid transfer proteins are active in human plasma, cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by nature do not express CETP. Additional inactivation of the PLTP gene resulted in reduced secretion of VLDL and subsequently in decreased susceptibility to diet-induced atherosclerosis. The aim of this study is to assess possible effects of differences in PLTP expression on VLDL secretion in mice that are proficient in CETP and PLTP. We compared human CETP transgenic (huCETPtg) mice with mice expressing both human lipid transfer proteins (huCETPtg/huPLTPtg). Plasma cholesterol in huCETPtg mice was 1.5-fold higher compared with huCETPtg/huPLTPtg mice (P < 0.001). This difference was mostly due to a lower HDL level in the huCETPtg/huPLTPtg mice, which subsequently could lead to the somewhat decreased CETP activity and concentration that was found in huCETPtg/huPLTPtg mice (P < 0.05). PLTP activity was 2.8-fold increased in these animals (P < 0.001). The human PLTP concentration was 5 microg/ml. Moderate overexpression of PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg mice (P < 0.05). The composition of nascent VLDL was similar in both strains. These results indicate that elevated PLTP activity in huCETPtg mice results in an increase in VLDL secretion. In addition, PLTP overexpression decreases plasma HDL cholesterol as well as CETP.

Phospholipid transfer protein

10.1194/jlr.m200166-jlr200

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Citations (88)

[Role of lipid transfers in intravascular lipoprotein metabolism in human].

PubMed (1995)

Philippe Gambert

Human lipoproteins after their intestinal or hepatic synthesis undergo within vascular compartment important remodeling through the agency of endothelial lipases, Lecithin: Cholesterol Acyl Transferase and lipid transfer proteins, Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP). Following CETP and PLTP characteristics presentation, transfer proteins activities and role were described specifying notably mechanism and kinetic models of cholesteryl ester transfer reaction (shuttle and ternary collision complex mechanisms). Comparative study of Phospholipid Transfer Activities mediated by CETP and PLTP has shown that phospholipid transfer activities of PLTP and CETP are different and might rely on distinct mechanisms. PLTP mediated phospholipid transfers modulate cholesteryl ester transfer activity of CETP. In vivo PLTP is responsible for the net mass transfer of phospholipid from triglyceride rich lipoprotein towards HDL. Whereas PLTP has no intrinsic cholesteryl ester transfer activity, it enhances the transfer of cholesteryl ester from HDL to VLDL and LDL. Thus PLTP might be a determinant factor in modulating the CETP mediated redistribution of cholesteryl esters between pro-(LDL) and anti-(HDL) atherogenic lipoproteins.

Cholesterylester transfer protein

Phospholipid transfer protein

Cholesteryl ester

Sterol O-acyltransferase

Reverse cholesterol transport

Intermediate-density lipoprotein

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Citations (1)

Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of preβ-high-density lipoproteins

Biochemical Journal (2001)

Jessica Lie Rini de Crom Matti Jauhiainen Teus van Gent Rien van Haperen