The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis D.M. is supported by a grant from the Philippe Foundation. Published, JLR Papers in Press, November 20, 2008.

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.

[1]  A. Tall,et al.  Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[2]  L. Lagrost,et al.  Atheroprotective Potential of Macrophage-Derived Phospholipid Transfer Protein in Low-Density Lipoprotein Receptor–Deficient Mice Is Overcome by Apolipoprotein AI Overexpression , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[3]  D. Aunis,et al.  Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity* , 2000, The Journal of Biological Chemistry.

[4]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[5]  Ing-Kae Wang,et al.  Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules , 2007, Nature Structural &Molecular Biology.

[6]  A. Tall,et al.  Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency , 2001, Nature Medicine.

[7]  D. Rader,et al.  Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. , 2004, The New England journal of medicine.

[8]  Heidi R. Kast-Woelbern,et al.  Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors Published, JLR Papers in Press, October 16, 2002. DOI 10.1194/jlr.C200014-JLR200 , 2002, Journal of Lipid Research.

[9]  A. Tall,et al.  Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. , 1996, The Journal of clinical investigation.

[10]  M. Jauhiainen,et al.  Important Role for Bone Marrow–Derived Cholesteryl Ester Transfer Protein in Lipoprotein Cholesterol Redistribution and Atherosclerotic Lesion Development in LDL Receptor Knockout Mice , 2007, Circulation research.

[11]  M. Jauhiainen,et al.  The Mechanism of the Remodeling of High Density Lipoproteins by Phospholipid Transfer Protein* , 2001, The Journal of Biological Chemistry.

[12]  A. Tall,et al.  Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes. , 1996, The Journal of clinical investigation.

[13]  A. Zwinderman,et al.  Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans: A Randomized Phase II Dose-Response Study , 2002, Circulation.

[14]  A. Tall,et al.  Separation of a plasma phospholipid transfer protein from cholesterol ester/phospholipid exchange protein. , 1983, The Journal of biological chemistry.

[15]  M. Jauhiainen,et al.  Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[16]  L. Smith,et al.  EFFECT OF VERY LOW-DENSITY LIPOPROTEINS ON LIPID TRANSFER IN INCUBATED SERUM. , 1965, Journal of lipid research.

[17]  R. Collins,et al.  Common variants at 30 loci contribute to polygenic dyslipidemia , 2009, Nature Genetics.

[18]  E. Rubin,et al.  Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. , 1995, The Journal of clinical investigation.

[19]  J. Jukema,et al.  Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[20]  S. Wright,et al.  Neutralization and Transfer of Lipopolysaccharide by Phospholipid Transfer Protein (*) , 1996, The Journal of Biological Chemistry.

[21]  A. Tall,et al.  HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. , 2008, Cell metabolism.

[22]  K. Marotti,et al.  Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein , 1993, Nature.

[23]  A. Tall,et al.  HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. , 2006, The Journal of clinical investigation.

[24]  A. Tall,et al.  Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. , 2000, The Journal of clinical investigation.

[25]  A. Tall.  Plasma lipid transfer proteins. , 1986, Journal of lipid research.

[26]  D. B. Zilversmit,et al.  Cholesteryl ester exchange protein in human plasma isolation and characterization. , 1978, Biochimica et biophysica acta.

[27]  A. Tall,et al.  Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins , 1989, Nature.

[28]  Olle Melander,et al.  Polymorphisms associated with cholesterol and risk of cardiovascular events. , 2008, The New England journal of medicine.

[29]  C. Bingle,et al.  PLUNC: a novel family of candidate host defence proteins expressed in the upper airways and nasopharynx. , 2002, Human molecular genetics.

[30]  A. Tall,et al.  Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis. , 1985, Journal of lipid research.

[31]  A. Tall,et al.  Purification and characterization of a human plasma cholesteryl ester transfer protein. , 1987, The Journal of biological chemistry.

[32]  Terri L. Gilbert,et al.  Complete cDNA encoding human phospholipid transfer protein from human endothelial cells. , 1994, The Journal of biological chemistry.

[33]  John A Wagner,et al.  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 , 2007, The Lancet.

[34]  A. Tall,et al.  Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. , 1990, The New England journal of medicine.

[35]  J. Danesh,et al.  Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. , 2008, JAMA.

[36]  E. Fisher,et al.  Phospholipid Transfer Protein Deficiency Impairs Apolipoprotein-B Secretion from Hepatocytes by Stimulating a Proteolytic Pathway through a Relative Deficiency of Vitamin E and an Increase in Intracellular Oxidants* , 2005, Journal of Biological Chemistry.

[37]  F. Grosveld,et al.  Increased Risk of Atherosclerosis by Elevated Plasma Levels of Phospholipid Transfer Protein* , 2002, The Journal of Biological Chemistry.

[38]  A. Tall,et al.  Phospholipid Transfer Protein Deficiency Protects Circulating Lipoproteins from Oxidation Due to the Enhanced Accumulation of Vitamin E* , 2002, The Journal of Biological Chemistry.

[39]  E. Tuzcu,et al.  Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis: Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) , 2008, Circulation.

[40]  J. Iqbal,et al.  Phospholipid Transfer Protein–Deficient Mice Absorb Less Cholesterol , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[41]  D. Rader,et al.  Cholesteryl Ester Transfer Protein: A Novel Target for Raising HDL and Inhibiting Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[42]  P. Barter,et al.  Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins. , 1980, Journal of lipid research.

[43]  C. Eng,et al.  Genetic variation in phospholipid transfer protein modulates lipoprotein profiles in hyperalphalipoproteinemia. , 2008, Metabolism: clinical and experimental.

[44]  A. Tall,et al.  A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly Published, JLR Papers in Press, February 16, 2004. DOI 10.1194/jlr.M300520-JLR200 , 2004, Journal of Lipid Research.

[45]  D. Driscoll,et al.  Molecular Cloning and Expression of Lipid Transfer Inhibitor Protein Reveals Its Identity with Apolipoprotein F* , 1999, The Journal of Biological Chemistry.

[46]  J. Ehrhart,et al.  Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone , 2008, British journal of pharmacology.

[47]  A. Tall,et al.  Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. , 1999, The Journal of clinical investigation.

[48]  C. Fielding,et al.  Cloning and sequencing of human cholesteryl ester transfer protein cDNA , 1987, Nature.