The metabolism and anti-atherogenic properties of HDL
2008; Elsevier BV; Volume: 50; Linguagem: Inglês
10.1194/jlr.r800034-jlr200
ISSN1539-7262
AutoresKerry-Anne Rye, Christina A. Bursill, Gilles Lambert, Fatiha Tabet, Philip J. Barter,
Tópico(s)Diet, Metabolism, and Disease
ResumoPopulation studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties. Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties. HDL, the smallest and most dense of all plasma lipoproteins, consist of several distinct subpopulations of particles that vary in size, shape, density, surface charge, and composition. An inverse relationship between HDL levels and premature cardiovascular disease has been observed in many large-scale prospective studies (1Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1286) Google Scholar, 2Gordon D.J. Probstfield J.L. Garrison R.J. Neaton J.D. Castelli W.P. Knoke J.D. Jacobs Jr., D.R. Bangdiwala S. Tyroler H.A. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.Circulation. 1989; 79: 8-15Crossref PubMed Scopus (2630) Google Scholar). This relationship is also evident in animal studies (3Morehouse 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 (152) Google Scholar, 4Belalcazar L.M. Merched A. Carr B. Oka K. Chen K.H. Pastore L. Beaudet A. Chan L. Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia.Circulation. 2003; 107: 2726-2732Crossref PubMed Google Scholar).HDL have several potentially anti-atherogenic properties. The best known of these is their ability to remove cholesterol from cells, such as macrophages in the artery wall, in the first step of the reverse cholesterol transport pathway (5Lewis G.F. Rader D.J. New insights into the regulation of HDL metabolism and reverse cholesterol transport.Circ. Res. 2005; 96: 1221-1232Crossref PubMed Scopus (816) Google Scholar). HDL also inhibit LDL oxidation (6Negre-Salvayre A. Dousset N. Ferretti G. Bacchetti T. Curatola G. Salvayre R. Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells.Free Radic. Biol. Med. 2006; 41: 1031-1040Crossref PubMed Scopus (112) Google Scholar), promote endothelial repair (7Tso C. Martinic G. Fan W.H. Rogers C. Rye K.A. Barter P.J. High-density lipoproteins enhance progenitor-mediated endothelium repair in mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1144-1149Crossref PubMed Scopus (155) Google Scholar), improve endothelial function (8Mineo C. Deguchi H. Griffin J.H. Shaul P.W. Endothelial and antithrombotic actions of HDL.Circ. Res. 2006; 98: 1352-1364Crossref PubMed Scopus (511) Google Scholar), have anti-thrombotic and anti-inflammatory properties (8Mineo C. Deguchi H. Griffin J.H. Shaul P.W. Endothelial and antithrombotic actions of HDL.Circ. Res. 2006; 98: 1352-1364Crossref PubMed Scopus (511) Google Scholar, 9Cockerill G.W. Rye K.A. Gamble J.R. Vadas M.A. Barter P.J. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1987-1994Crossref PubMed Scopus (670) Google Scholar), and inhibit the binding of monocytes to the endothelium (10Murphy A.J. Woollard K.J. Hoang A. Mukhamedova N. Stirzaker R.A. McCormick S.P. Remaley A.T. Sviridov D. Chin-Dusting J. High-Density Lipoprotein Reduces the Human Monocyte Inflammatory Response.Arterioscler Thromb Vasc Biol. 2008; Crossref PubMed Scopus (334) Google Scholar). In addition to preventing atherosclerotic lesion progression, HDL also promote lesion regression in animals (11Tangirala R.K. Tsukamoto K. Chun S.H. Usher D. Pure E. Rader D.J. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice.Circulation. 1999; 100: 1816-1822Crossref PubMed Scopus (320) Google Scholar, 12Badimon J.J. Badimon L. Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.J. Clin. Invest. 1990; 85: 1234-1241Crossref PubMed Scopus (669) Google Scholar).This review presents evidence that several of the aforementioned anti-atherogenic functions of HDL are mediated by specific subpopulations of particles. To appreciate this functional diversity, it is important to understand something of the origins and heterogeneity of HDL subpopulations.ORIGINS OF HDLHDL originate as discoidal particles that are either secreted from the liver or assembled in the plasma from the individual constituents. Discoidal HDL consist of two or more apolipoprotein molecules complexed with phospholipids and unesterified cholesterol (Fig. 1A). These particles are excellent substrates for LCAT, the enzyme that generates most of the cholesteryl esters in plasma (13Jonas A. Lecithin cholesterol acyltransferase.Biochim. Biophys. Acta. 2000; 1529: 245-256Crossref PubMed Scopus (304) Google Scholar). Cholesteryl esters are extremely hydrophobic and partition into the center of the particles as they are formed. This converts discoidal HDL into the large spherical HDL particles that predominate in normal human plasma. It also depletes the HDL surface of cholesterol and establishes a concentration gradient down which cholesterol from other lipoproteins and cell membranes moves into the HDL fraction, thus ensuring a continual supply of unesterified cholesterol for the LCAT reaction.Spherical HDL contain a core of neutral lipids (cholesteryl esters and some triglyceride) surrounded by a surface monolayer of phospholipids, unesterified cholesterol, and apolipoproteins (Fig. 1A). They can be separated by ultracentrifugation on the basis of density into two major subfractions: HDL2 and HDL3, with HDL2 being larger and less dense than HDL3 (Fig. 1B). HDL can also be resolved by nondenaturing gradient gel electrophoresis into five distinct subpopulations of particles 7.6–10.6 nm in diameter (Fig. 1C) (14Blanche P.J. Gong E.L. Forte T.M. Nichols A.V. Characterization of human high-density lipoproteins by gradient gel electrophoresis.Biochim. Biophys. Acta. 1981; 665: 408-419Crossref PubMed Scopus (443) Google Scholar).The HDL in human plasma are classified on the basis of their main apolipoproteins, apoA-I and apoA-II, into two populations of particles: those containing apoA-I, but not apoA-II, (A-I)HDL, and those that contain apoA-I and apoA-II, (A-I/A-II)HDL (Fig. 1D) (15Cheung M.C. Albers J.J. Characterization of lipoprotein particles isolated by immunoaffinity chromatography. Particles containing A-I and A-II and particles containing A-I but no A-II.J. Biol. Chem. 1984; 259: 12201-12209Abstract Full Text PDF PubMed Google Scholar). In normal human plasma, apoA-I is distributed approximately equally between (A-I)HDL and (A-I/A-II)HDL, while most of the apoA-II is associated with (A-I/A-II)HDL. When separated by agarose gel electrophoresis on the basis of surface charge, HDL migrate to a γ-, α-or preβ- position (Fig. 1E) (16Castro G.R. Fielding C.J. Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein.Biochemistry. 1988; 27: 25-29Crossref PubMed Scopus (562) Google Scholar). Most spherical HDL are α-migrating, while discoidal HDL, lipid-free apoA-I, and lipid-free apoA-II migrate to a preβ-position. A minor subpopulation of large, spherical HDL containing apoE as the only apolipoprotein migrate to a γ-position (17Huang Y. Eckardstein A.von Wu S. Maeda N. Assmann G. A plasma lipoprotein containing only apolipoprotein E and with gamma mobility on electrophoresis releases cholesterol from cells.Proc. Natl. Acad. Sci. USA. 1994; 91: 1834-1838Crossref PubMed Scopus (169) Google Scholar).REMODELLING AND HDL SUBPOPULATION HETEROGENEITYSeveral plasma factors alter the size, shape, surface charge, and composition of HDL in processes that are collectively termed remodelling. These plasma factors include LCAT, cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), hepatic lipase (HL), and endothelial lipase (EL) (Fig. 2).Fig. 2HDL Remodelling. Influence of plasma factors on the subpopulation distribution of HDL. LCAT generates cholesteryl esters and remodels discoidal HDL into spherical HDL (i); cholesteryl ester transfer protein (CETP) transfers cholesteryl esters and triglycerides between HDL, LDL, and VLDL; remodels HDL into small particles; and generates lipid-free/lipid-poor apoA-I (ii); phospholipid transfer protein (PLTP) transfers phospholipids between HDL and VLDL and between individual HDL particles; remodels HDL into large and small particles; and generates lipid-free/lipid-poor apoA-I (iii); endothelial lipase (EL) hydrolyses phospholipids and remodels HDL into small particles(iv); and hepatic lipase (HL) hydrolyses phospholipids and triglycerides, remodels HDL into small particles, and generates lipid-free/lipid-poor apoA-I (v).View Large Image Figure ViewerDownload Hi-res image Download (PPT)One of the key events in remodelling is the dissociation of lipid-free or lipid-poor apoA-I from spherical HDL by CETP, PLTP, and HL (18Rye K.A. Barter P.J. Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 421-428Crossref PubMed Scopus (262) Google Scholar). Lipid-free/lipid-poor apoA-I accounts for up to 5% of the total plasma apoA-I and accepts the cholesterol and phospholipids that efflux from cell membranes via the ATP binding cassette transporter A1 (ABCA1). Progressive lipidation of apoA-I via this pathway generates discoidal HDL and recycles apoA-I back into the HDL fraction. This reduces the rate at which apoA-I is cleared from the circulation and helps to maintain circulating HDL levels.CETP is a member of the lipopolysaccharide-binding/lipid transfer protein family that transfers cholesteryl esters and triglycerides and, to a lesser extent phospholipids, between HDL, VLDL, and LDL (19Qiu 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). As CETP-mediated transfers of cholesteryl esters between HDL and LDL are rapid relative to the rate at which the lipoproteins are catabolised, these cholesteryl ester pools are in equilibrium in vivo. This is not necessarily the case for CETP-mediated transfers of cholesteryl esters and triglycerides between HDL and VLDL. When VLDL levels are elevated, CETP-mediated transfers of core lipids from HDL to VLDL exceed those from VLDL to HDL, generating core lipid-depleted, triglyceride-enriched HDL that have an excess of surface constituents and are structurally labile. This imbalance is rectified by the dissociation of lipid-free/lipid-poor apoA-I and a reduction in HDL size (Fig. 2). Triglyceride-enriched HDL are also excellent substrates for HL, which further reduces HDL size and enhances the dissociation of lipid-free/lipid-poor apoA-I (Fig. 2) (20Clay M.A. Newnham H.H. Barter P.J. Hepatic lipase promotes a loss of apolipoprotein A-I from triglyceride-enriched human high density lipoproteins during incubation in vitro.Arterioscler. Thromb. 1991; 11: 415-422Crossref PubMed Google Scholar). CETP can also remodel HDL into small particles by a fusion process that does not involve the dissociation of lipid-free/lipid-poor apoA-I (21Rye K.A. Hime N.J. Barter P.J. Evidence that cholesteryl ester transfer protein-mediated reductions in reconstituted high density lipoprotein size involve particle fusion.J. Biol. Chem. 1997; 272: 3953-3960Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Inhibiting CETP activity as a therapeutic strategy for increasing HDL levels is under investigation. Although this decreases atherosclerosis in animals (3Morehouse 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 (152) Google Scholar), there is, as yet, no evidence that it reduces cardiovascular events in humans.PLTP is a member of the same protein family as CETP. It transfers phospholipids between HDL and VLDL, as well as between different HDL particles. PLTP remodels HDL into large and small particles by particle fusion and the dissociation of lipid-free/lipid-poor apoA-I (Fig. 2) (22Settasatian N. Duong M. Curtiss L.K. Ehnholm C. Jauhiainen M. Huuskonen J. Rye K.A. The mechanism of the remodeling of high density lipoproteins by phospholipid transfer protein.J. Biol. Chem. 2001; 276: 26898-26905Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). The role of PLTP in atherogenesis is controversial, with reports that its expression in macrophages both enhances and inhibits atherosclerosis in mice (23van Haperen R. Samyn H. Moerland M. Gent T.van Peeters M. Grosveld F. Tol A.van Crom R.de Elevated expression of phospholipid transfer protein in bone marrow derived cells causes atherosclerosis.PLoS One. 2008; 3: e2255Crossref PubMed Scopus (23) Google Scholar, 24Valenta D.T. Ogier N. Bradshaw G. Black A.S. Bonnet D.J. Lagrost L. Curtiss L.K. Desrumaux C.M. Atheroprotective potential of macrophage-derived phospholipid transfer protein in low-density lipoprotein receptor-deficient mice is overcome by apolipoprotein AI overexpression.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1572-1578Crossref PubMed Scopus (58) Google Scholar). It would seem, on balance, that PLTP has an unfavorable effect on atherosclerosis.EL and HL are members of the triglyceride lipase family with strikingly different substrate specificities. EL has high phospholipase and very low triglyceride lipase activity, while HL has high triglyceride lipase activity and low phospholipase activity (25Jaye M. Lynch K.J. Krawiec J. Marchadier D. Maugeais C. Doan K. South V. Amin D. Perrone M. Rader D.J. A novel endothelial-derived lipase that modulates HDL metabolism.Nat. Genet. 1999; 21: 424-428Crossref PubMed Scopus (416) Google Scholar). Although both enzymes remodel HDL into small particles, HL does this more effectively than EL. EL also differs from HL by not dissociating lipid-free/lipid-poor apoA-I from HDL (Fig. 2) (25Jaye M. Lynch K.J. Krawiec J. Marchadier D. Maugeais C. Doan K. South V. Amin D. Perrone M. Rader D.J. A novel endothelial-derived lipase that modulates HDL metabolism.Nat. Genet. 1999; 21: 424-428Crossref PubMed Scopus (416) Google Scholar, 26Jahangiri A. Rader D.J. Marchadier D. Curtiss L.K. Bonnet D.J. Rye K.A. Evidence that endothelial lipase remodels high density lipoproteins without mediating the dissociation of apolipoprotein A-I.J. Lipid Res. 2005; 46: 896-903Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Although their influence on atherosclerosis is poorly defined, EL and HL both regulate plasma HDL levels (27Ma K. Cilingiroglu M. Otvos J.D. Ballantyne C.M. Marian A.J. Chan L. Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism.Proc. Natl. Acad. Sci. USA. 2003; 100: 2748-2753Crossref PubMed Scopus (201) Google Scholar, 28Jansen H. Hepatic lipase: friend or foe and under what circumstances?.Curr. Atheroscler. Rep. 2004; 6: 343-347Crossref PubMed Scopus (19) Google Scholar). Additional studies of these enzymes are warranted.Insights into the regulation of HDL remodelling have been obtained from homogeneous preparations of spherical, reconstituted HDL (rHDL) in which the composition is tightly regulated. This approach has established that apoA-II does not dissociate from HDL. ApoA-II also inhibits the CETP-mediated remodelling of HDL and the dissociation of lipid-free/lipid-poor apoA-I (29Rye K.A. Wee K. Curtiss L.K. Bonnet D.J. Barter P.J. Apolipoprotein A-II inhibits high density lipoprotein remodeling and lipid-poor apolipoprotein A-I formation.J. Biol. Chem. 2003; 278: 22530-22536Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The ability of CETP to remodel HDL and mediate the dissociation of apoA-I is also influenced by the phospholipid composition of the particles (30Rye K.A. Duong M. Psaltis M.K. Curtiss L.K. Bonnet D.J. Stocker R. Barter P.J. Evidence that phospholipids play a key role in pre-beta apoA-I formation and high-density lipoprotein remodeling.Biochemistry. 2002; 41: 12538-12545Crossref PubMed Scopus (30) Google Scholar), while triglyceride-enrichment enhances both HDL remodelling by PLTP and the dissociation of apoA-I (22Settasatian N. Duong M. Curtiss L.K. Ehnholm C. Jauhiainen M. Huuskonen J. Rye K.A. The mechanism of the remodeling of high density lipoproteins by phospholipid transfer protein.J. Biol. Chem. 2001; 276: 26898-26905Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). ApoA-I and apoA-II also regulate the hydrolysis of HDL phospholipids by EL, and the HL-mediated hydrolysis of HDL phospholipids and triglycerides (31Caiazza D. Jahangiri A. Rader D.J. Marchadier D. Rye K.A. Apolipoproteins regulate the kinetics of endothelial lipase-mediated hydrolysis of phospholipids in reconstituted high-density lipoproteins.Biochemistry. 2004; 43: 11898-11905Crossref PubMed Scopus (14) Google Scholar, 32Hime N.J. Barter P.J. Rye K.A. The influence of apolipoproteins on the hepatic lipase-mediated hydrolysis of high density lipoprotein phospholipid and triacylglycerol.J. Biol. Chem. 1998; 273: 27191-27198Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar).RELATIONSHIP BETWEEN THE CARDIOPROTECTIVE PROPERTIES AND SUBPOPULATION DISTRIBUTION OF HDLThe results of human population and transgenic animal studies suggest that HDL subpopulations do not all protect against atherosclerosis equally well. However, evidence relating to the relative importance of (A-I)HDL vs. (A-I/A-II)HDL, large vs. small HDL, and preβ-migrating vs. α-migrating HDL is confusing. For example, the suggestion that lipid-free/lipid-poor apoA-I and discoidal HDL, which both exhibit preβ migration, may be more cardioprotective than spherical, α-migrating HDL is based largely on the observation that preβ-migrating lipid-free/lipid-poor apoA-I is preferred over α-migrating HDL as an acceptor of the cholesterol that effluxes from cells via ABCA1 in the first step of reverse cholesterol transport (33Oram J.F. Vaughan A.M. ATP-Binding cassette cholesterol transporters and cardiovascular disease.Circ. Res. 2006; 99: 1031-1043Crossref PubMed Scopus (322) Google Scholar).While superficially appealing, epidemiological evidence supporting a cardioprotective role for preβ-migrating lipid-free/lipid-poor apoA-I is lacking. When this issue was addressed in a recent analysis of the Veterans Affairs HDL Intervention Trial, subjects with new cardiovascular events had significantly lower levels of large, α-migrating spherical HDL than event-free subjects (34Asztalos B.F. Collins D. Horvath K.V. Bloomfield H.E. Robins S.J. Schaefer E.J. Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial.Metabolism. 2008; 57: 77-83Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). When apoA-I-containing HDL subpopulations from these individuals were quantified by 2-D gel electrophoresis, the cases had lower levels of large α-migrating HDL and significantly higher levels of small, poorly lipidated, preβ-migrating HDL compared with event-free subjects (34Asztalos B.F. Collins D. Horvath K.V. Bloomfield H.E. Robins S.J. Schaefer E.J. Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial.Metabolism. 2008; 57: 77-83Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The concentration of large, α-migrating spherical HDL was also the best negative predictor of recurrent cardiovascular events, while the concentration of smaller, α-migrating HDL was a positive predictor of new events (34Asztalos B.F. Collins D. Horvath K.V. Bloomfield H.E. Robins S.J. Schaefer E.J. Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial.Metabolism. 2008; 57: 77-83Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). This is consistent with a recent report showing that large, spherical HDL are the preferred acceptors of the cholesterol that effluxes from macrophages via the ATP binding cassette transporter G1 (ABCG1) (35Matsuura 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).The possibility that HDL subpopulations are functionally distinct raises the important question as to which subpopulations should be therapeutic targets for raising HDL levels. One intervention that elevates HDL levels is inhibition of CETP activity. This causes cholesteryl esters to accumulate in HDL and selectively increases the level of large HDL2 particles (36Brousseau 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). Inhibition of CETP activity in rabbits by torcetrapib is markedly anti-atherogenic (3Morehouse 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 (152) Google Scholar). In humans, by contrast, torcetrapib does not reduce atherosclerosis (37Nissen S.E. Tardif J.C. Nicholls S.J. Revkin J.H. Shear C.L. Duggan W.T. Ruzyllo W. Bachinsky W.B. Lasala G.P. Tuzcu E.M. Effect of torcetrapib on the progression of coronary atherosclerosis.N. Engl. J. Med. 2007; 356: 1304-1316Crossref PubMed Scopus (886) Google Scholar, 38Bots M.L. Visseren F.L. Evans G.W. Riley W.A. Revkin J.H. Tegeler C.H. Shear C.L. Duggan W.T. Vicari R.M. Grobbee D.E. al et Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.Lancet. 2007; 370: 153-160Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar). It also caused an excess of deaths and cardiovascular events in a large-scale endpoint trial (39Barter 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 (2578) Google Scholar). At present it is not known if this deleterious outcome was related directly to the inhibition of CETP; to the generation of large, possibly dysfunctional HDL particles; or to off-target effects of torcetrapib. Whether CETP inhibition is cardioprotective in humans is currently being investigated with other compounds that appear not to share the off-target effects of torcetrapib.RELATIONSHIP BETWEEN THE CARDIOPROTECTIVE PROPERTIES OF HDL SUBPOPULATIONS AND THEIR FUNCTIONAL HETEROGENEITYInfluence of HDL subpopulations on cholesterol efflux from cellsHDL promote cholesterol efflux from cell membranes by four distinct pathways: i) via ABCA1 to lipid-poor/lipid-free apoA-I; ii) by passive diffusion to a wide range of HDL acceptors; iii) via scavenger receptor-B1 (SR-B1) to various spherical HDL subpopulations; and iv) via ABCG1 to large, spherical HDL.SR-B1 is involved in the first and the last step of reverse cholesterol transport. Although its ability to mediate cholesterol efflux from cells in the first step of the pathway lacks specificity, this may not be the case for its ability to deplete HDL of cholesteryl esters in the final step (40Acton 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.Science. 1996; 271: 518-520Crossref PubMed Scopus (1986) Google Scholar). While some investigators have reported that SR-B1 removes cholesteryl esters from (A-I/A-II)HDL more effectively than from (A-I)HDL (41de Beer M.C. Durbin D.M. Cai L. Mirocha N. Jonas A. Webb N.R. Beer F.C. de Westhuyzen D.R. van Der Apolipoprotein A-II modulates the binding and selective lipid uptake of reconstituted high density lipoprotein by scavenger receptor BI.J. Biol. Chem. 2001; 276: 15832-15839Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), others have found that it preferentially removes cholesteryl esters from (A-I)HDL (42Rinninger F. Brundert M. Budzinski R.M. Fruchart J.C. Greten H. Castro G.R. Scavenger receptor BI (SR-BI) mediates a higher selective cholesteryl ester uptake from LpA-I compared with LpA-I:A-II lipoprotein particles.Atherosclerosis. 2003; 166: 31-40Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar).Antioxidant properties of HDL subpopulationsAtherosclerosis is an inflammatory disease that is initiated, in part, by the presence of oxidized LDL in the artery wall. The ability of different HDL subpopulations to inhibit LDL lipid and apolipoprotein oxidation is not well understood. While some investigators have found that HDL3 inhibit LDL oxidation better than HDL2 (43Yoshikawa M. Sakuma N. Hibino T. Sato T. Fujinami T. HDL3 exerts more powerful anti-oxidative, protective effects against copper-catalyzed LDL oxidation than HDL2.Clin. Biochem. 1997; 30: 221-225Crossref PubMed Scopus (64) Google Scholar, 44Kontush A. Chantepie S. Chapman M.J. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1881-1888Crossref PubMed Scopus (342) Google Scholar), others have reported that the antioxidant capacity of small, dense HDL is impaired, at least in subjects with the metabolic syndrome (45Hansel B. Giral P. Nobecourt E. Chantepie S. Bruckert E. Chapman M.J. Kontush A. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity.J. Clin. Endocrinol. Metab. 2004; 89: 4963-4971Crossref PubMed Scopus (376) Google Scholar). Other studies have demonstrated that CETP transfers lipid hydroperoxides from LDL to HDL, where they are reduced to lipid hydroxides and cleared by the liver (46Garner B. Waldeck A.R. Witting P.K. Rye K.A. Stocker R. Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoproteins AI and AII.J. Biol. Chem. 1998; 273: 6088-6095Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar). In that study, lipid hydroperoxide reduction was comparable in HDL2 and HDL3.HDL-associated proteins such as paraoxonase and platelet-activating factor acetyl hydrolase also contribute to the anti-oxidant properties of HDL. A recent report has suggested that the anti-oxidant properties of paraoxonase are enhanced in (A-I/A-II)HDL (47Moren X. Deakin S. Liu M.L. Taskinen M.R. James R.W. HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress.J. Lipid Res. 2008; 49: 1246-1253Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). It is not known if this is also the case for platelet-activating factor acetyl hydrolase.Anti-infla
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