Biogenesis and speciation of nascent apoA-I-containing particles in various cell lines

It is generally thought that the large heterogeneity of human HDL confers antiatherogenic properties; however, the mechanisms governing HDL biogenesis and speciation are complex and poorly understood. Here, we show that incubation of exogenous apolipoprotein A-I (apoA-I) with fibroblasts, CaCo-2, or CHO-overexpressing ABCA1 cells generates only α-nascent apolipoprotein A-I-containing particles (α-LpA-I) with diameters of 8–20 nm, whereas human umbilical vein endothelial cells and ABCA1 mutant (Q597R) cells were unable to form such particles. Interestingly, incubation of exogenous apoA-I with either HepG2 or macrophages generates both α-LpA-I and preβ1-LpA-I. Furthermore, glyburide inhibits almost completely the formation of α-LpA-I but not preβ1-LpA-I. Similarly, endogenously secreted HepG2 apoA-I was found to be associated with both preβ1-LpA-I and α-LpA-I; by contrast, CaCo-2 cells secreted only α-LpA-I. To determine whether α-LpA-I generated by fibroblasts is a good substrate for LCAT, isolated α-LpA-I as well as reconstituted HDL [r(HDL)] was reacted with LCAT. Although both particles had similar Vmax (8.4 vs. 8.2 nmol cholesteryl ester/h/μg LCAT, respectively), the Km value was increased 2-fold for α-LpA-I compared with r(HDL) (1.2 vs. 0.7 μM apoA-I).These results demonstrate that 1) ABCA1 is required for the formation of α-LpA-I but not preβ1-LpA-I; and 2) α-LpA-I interacts efficiently with LCAT. Thus, our study provides direct evidence for a new link between specific cell lines and the speciation of nascent HDL that occurs by both ABCA1-dependent and -independent pathways. It is generally thought that the large heterogeneity of human HDL confers antiatherogenic properties; however, the mechanisms governing HDL biogenesis and speciation are complex and poorly understood. Here, we show that incubation of exogenous apolipoprotein A-I (apoA-I) with fibroblasts, CaCo-2, or CHO-overexpressing ABCA1 cells generates only α-nascent apolipoprotein A-I-containing particles (α-LpA-I) with diameters of 8–20 nm, whereas human umbilical vein endothelial cells and ABCA1 mutant (Q597R) cells were unable to form such particles. Interestingly, incubation of exogenous apoA-I with either HepG2 or macrophages generates both α-LpA-I and preβ1-LpA-I. Furthermore, glyburide inhibits almost completely the formation of α-LpA-I but not preβ1-LpA-I. Similarly, endogenously secreted HepG2 apoA-I was found to be associated with both preβ1-LpA-I and α-LpA-I; by contrast, CaCo-2 cells secreted only α-LpA-I. To determine whether α-LpA-I generated by fibroblasts is a good substrate for LCAT, isolated α-LpA-I as well as reconstituted HDL [r(HDL)] was reacted with LCAT. Although both particles had similar Vmax (8.4 vs. 8.2 nmol cholesteryl ester/h/μg LCAT, respectively), the Km value was increased 2-fold for α-LpA-I compared with r(HDL) (1.2 vs. 0.7 μM apoA-I). These results demonstrate that 1) ABCA1 is required for the formation of α-LpA-I but not preβ1-LpA-I; and 2) α-LpA-I interacts efficiently with LCAT. Thus, our study provides direct evidence for a new link between specific cell lines and the speciation of nascent HDL that occurs by both ABCA1-dependent and -independent pathways. The molecular interaction of apolipoprotein A-I (apoA-I) with cell membranes has important implications in reverse cholesterol transport (RCT) because it provides a mechanism whereby excess cholesterol is removed from peripheral cells unable to catabolize cholesterol. This process is crucial for HDL biogenesis and is believed to be one of the major mechanisms by which HDL may protect against atherosclerotic vascular disease (1Brewer Jr., H.B. Santamarina-Fojo S. New insights into the role of the adenosine triphosphate-binding cassette transporters in high-density lipoprotein metabolism and reverse cholesterol transport.Am. J. Cardiol. 2003; 91: 3E-11EGoogle Scholar, 2Tall A.R. Plasma cholesteryl ester transfer protein.J. Lipid Res. 1993; 34: 1255-1274Google Scholar). However, in spite of the importance of the HDL biogenesis pathway in RCT, very little is known about the mechanisms involved in determining the structural characteristics of nascent HDL particles. It has been suggested that HDL heterogeneity involves not only intracellular factors that control the synthesis and cell uptake of HDL but also factors that promote the assembly and remodeling of HDL in the extracellular space. Indeed, several enzymes, such as lecithin:cholesterol acyltransferase, hepatic lipase, cholesteryl ester (CE) transfer protein, and phospholipid transfer protein, have been implicated in regulating apoA-I cycles between lipid-poor and lipid-associated forms as a part of a highly dynamic metabolism of HDL (3Barter P.J. Hugh Sinclair Lecture. The regulation and remodelling of HDL by plasma factors.Atheroscler. Suppl. 2002; 3: 39-47Google Scholar). HDL subspecies can be classified according to a variety of properties, including hydrated density (4Havel R.J. Eder H.A. Bragdon J.H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.J. Clin. Invest. 1955; 34: 1345-1353Google Scholar), apolipoprotein composition, and charge characteristics (5Marcel Y.L. Weech P.K. Nguyen T.D. Milne R.W. McConathy W.J. Apolipoproteins as the basis for heterogeneity in high-density lipoprotein2 and high-density lipoprotein3. Studies by isoelectric focusing on agarose films.Eur. J. Biochem. 1984; 143: 467-476Google Scholar). For example, an earlier study by Fielding and colleagues (6Kawano M. Miida T. Fielding C.J. Fielding P.E. Quantitation of pre beta-HDL-dependent and nonspecific components of the total efflux of cellular cholesterol and phospholipid.Biochemistry. 1993; 32: 5025-5028Google Scholar) documented that a minor subspecies of human HDL that migrates with preβ mobility on agarose gels can remove free cholesterol from cultured fibroblasts at a faster rate than α-migrating HDL, which constitutes the bulk of plasma HDL. Furthermore, it was documented that preβ-HDL particles were present in the peripheral lymph of dogs (7Lefevre M. Sloop C.H. Roheim P.S. Characterization of dog prenodal peripheral lymph lipoproteins. Evidence for the peripheral formation of lipoprotein-unassociated apoA-I with slow pre-beta electrophoretic mobility.J. Lipid Res. 1988; 29: 1139-1148Google Scholar) and the interstitial space (8Barter P.J. Rye K.A. Molecular mechanisms of reverse cholesterol transport.Curr. Opin. Lipidol. 1996; 7: 82-87Google Scholar), suggesting a key role for these particles in the initial removal of cholesterol. Moreover, this concept is supported by studies demonstrating that preβ-HDL acts as an initial acceptor of cellular cholesterol and shuttles it into a series of larger preβ particles and ultimately to α-migrating particles that contain LCAT for esterification (9Francone O.L. Gurakar A. Fielding C. Distribution and functions of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in plasma lipoproteins. Evidence for a functional unit containing these activities together with apolipoproteins A-I and D that catalyzes the esterification and transfer of cell-derived cholesterol.J. Biol. Chem. 1989; 264: 7066-7072Google Scholar, 10Huang Y. Eckardstein A. von Assmann G. Cell-derived unesterified cholesterol cycles between different HDLs and LDL for its effective esterification in plasma.Arterioscler. Thromb. 1993; 13: 445-458Google Scholar). A growing body of evidence indicates that ABCA1 is a critical cell surface protein required for the transfer of cellular lipids and the maintenance of HDL levels in plasma and is likely important for the first step of RCT from peripheral tissues, including macrophages in the vessel wall (11Tall A.R. Role of ABCA1 in cellular cholesterol efflux and reverse cholesterol transport.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 710-711Google Scholar). Furthermore, Brewer and colleagues (12Basso F. Freeman L. Knapper C.L. Remaley A. Stonik J. Neufeld E.B. Tansey T. Amar M.J. Fruchart-Najib J. Duverger N. et al.Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations.J. Lipid Res. 2003; 44: 296-302Google Scholar) have documented that hepatic ABCA1 is crucial for the formation and maintenance of plasma HDL levels. The importance of ABCA1 in the lipidation of apoA-I is highlighted by the finding that >50 mutations in the ABCA1 gene have been associated with a variety of clinically distinct HDL-deficiency diseases, including Tangier disease (TD) and familial HDL deficiency (13Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. Dam M. van Yu L. Brewer C. Collins J.A. Molhuizen H.O. et al.Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. Scholar, M. A. Clee S.M. Roomp K. Zhang L.H. Yu L. Collins J.A. Dam M. van Molhuizen H.O. et al.Mutations in the ABC1 gene in familial HDL deficiency with cholesterol Scholar, and the and of in the ABCA1 Thromb. Vasc. Biol. 2003; 23: Scholar). Although studies in a cell that the ABCA1 transporter a role in the heterogeneity of nascent HDL particles M. Marcil M. M. L. J. Molecular and cellular of apolipoprotein A-I lipidation by the cassette transporter Biol. Chem. Scholar, L. M. M. Marcil M. J. Molecular between and on Lipid Res. Scholar), the molecular mechanisms involved in the speciation of HDL particles are not well understood. it was the of the present study to the role of ABCA1 in the biogenesis and speciation of nascent apolipoprotein A-I-containing particles in cell lines and to For the present we fibroblasts from control and with for at the ABCA1 and the mutations and the in as (13Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. Dam M. van Yu L. Brewer C. Collins J.A. Molhuizen H.O. et al.Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. Scholar, M. A. Clee S.M. Roomp K. Zhang L.H. Yu L. Collins J.A. Dam M. van Molhuizen H.O. et al.Mutations in the ABC1 gene in familial HDL deficiency with cholesterol Scholar). The for the study was and by the of the forms for and were fibroblasts were from of the of and control and were cultured in with and human umbilical vein endothelial cells human and CaCo-2 cells were cultured cells were by of and of and were and cultured as cholesterol efflux to apolipoprotein A-I by the cell surface of cassette transporter Biol. Chem. 2003; Scholar). plasma apoA-I was in and against apoA-I was with by to a specific of apoA-I and The of apoA-I and its in a and the and of these have been by and colleagues J. F. Y.L. of in human apolipoprotein on phospholipid Scholar). mutant was as a control for α-LpA-I cholesterol cell lines in were with for the at was removed from the by a molecular that between apoA-I and particles with molecular was in the with of containing a particles were for at a with a of to remove The was to remove apoA-I from particles secreted by HepG2 and CaCo-2 in cells was not by this we show that both the and the plasma preβ1-LpA-I an molecular of α-LpA-I particles were isolated as M. Marcil M. M. L. J. Characterization of human cassette transporter implications for determining the of nascent density lipoprotein Biol. Chem. Scholar). fibroblasts were with and μM and with for at were and with a and was in the with of in the of a particles were a with a of to remove The of isolated α-LpA-I was by with efflux and were as L. M. M. Marcil M. J. Molecular between and on Lipid Res. Scholar) with minor cells were on the cells were with for cells were for a cells were with for efflux was for the and efflux was as in in in the results were as of total cholesterol. from a and a were to in with for and as was for the of generated the incubation of apoA-I or apoA-I mutant with were with as fibroblasts from control and were to in and for with of with the first incubation with cells were for a the cells were as incubation with either or mutant apoA-I and were the as by and A. A. L. The of of apolipoproteins and the and functional of reconstituted lipoprotein Biol. Chem. 1993; Scholar). of was in this density lipoprotein [r(HDL)] particles were by to apoA-I or complex formation was by with particles were separated by as L. Marcil M. J. J. of lecithin:cholesterol acyltransferase complex with density lipoprotein protein Evidence for an in LCAT Biol. Chem. Scholar). were separated in the first to by agarose and in the to the by molecular protein was as a on separated were membranes particles were by the membranes with The of or was by human lecithin:cholesterol acyltransferase was a from S. of esterification were as in the of the of density lipoprotein apolipoprotein A-I and the of the lecithin:cholesterol acyltransferase Lipid Res. Scholar). these of substrate were α-LpA-I and r(HDL) with similar specific as α-LpA-I generated by either or mutant apoA-I were for to the LCAT of either or r(HDL) were reacted with of LCAT for at The LCAT of of either or of and and to a of of and r(HDL) were from the initial specific of for the were generally as these initial were with substrate on our studies demonstrating that the interaction of apoA-I with human fibroblasts generated only α-LpA-I M. Marcil M. M. L. J. Molecular and cellular of apolipoprotein A-I lipidation by the cassette transporter Biol. Chem. Scholar, M. Marcil M. M. L. J. Characterization of human cassette transporter implications for determining the of nascent density lipoprotein Biol. Chem. Scholar), the was whether the formation of both α-LpA-I and preβ1-LpA-I be on specific cell preβ1-LpA-I are from and because of the of of subspecies by we a to remove apoA-I from the a with a with a of to remove as in and The present between apoA-I and particles with molecular However, the removal of apoA-I from the may in an of preβ1-LpA-I. To the of the removal of the of the from either HepG2 cells or macrophages found to form preβ1-LpA-I was for by the of the from fibroblasts, ABCA1 mutant fibroblasts, or in the by as by we show that both the and the plasma preβ1-LpA-I an molecular of in incubation of fibroblasts, CaCo-2 or CHO-overexpressing ABCA1 with for at by the removal of apoA-I as and of by generated only α-LpA-I with a from to nm, whereas apoA-I with either or ABCA1 mutant (Q597R) was unable to form such particles. we found that ABCA1 mutant also to form α-LpA-I not incubation of human or cells with generated both preβ1-LpA-I and α-LpA-I studies have documented that glyburide cholesterol efflux from cells to apoA-I with an of μM and had little on the efflux in the of ABCA1 P.E. K. G. Fielding C.J. A mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein Scholar, A. T. M. of and cholesterol transport by the and Lipid Res. Scholar). in the of μM glyburide the incubation almost completely the formation of larger α-LpA-I in the of cell but not the preβ1-LpA-I generated by human and Furthermore, of ABCA1 with glyburide in fibroblasts, CaCo-2, or to the formation of α-LpA-I a of these particles were not in the of ABCA1 mutant of different cell lines with μM glyburide for not or as by A of nascent generated by HepG2 and fibroblasts that was associated with particles both preβ and electrophoretic mobility in HepG2 contrast, fibroblasts generated only α-LpA-I To the of ABCA1 to the formation of preβ1-LpA-I and was with HepG2 cells or fibroblasts in the of μM glyburide for the in glyburide almost completely α-LpA-I subspecies in both HepG2 cells and fibroblasts, but not preβ1-LpA-I generated by HepG2 a incubation Moreover, both the charge and the of preβ1-LpA-I and α-LpA-I were a incubation the ABCA1 protein was highly to with in fibroblasts, CaCo-2, and HepG2 cells or to with of whereas ABCA1 was not in as by of total cell from different cell lines by with an This is with our that the of α-LpA-I subspecies were increased by with in fibroblasts, CaCo-2, or contrast, preβ1-LpA-I by HepG2 or were to with or not that the incubation of apoA-I with HepG2 cells generates both preβ1-LpA-I and the was whether different preβ1-LpA-I particles found in the were by or whether were a of plasma lipoprotein was in which the of endogenously secreted particles from either HepG2 or CaCo-2 cells was or not from apoA-I as and by in HepG2 cells secreted lipoproteins with a from to and have both preβ and electrophoretic mobility similar to plasma preβ1-LpA-I and α-LpA-I contrast, CaCo-2 cells secreted only α-LpA-I Furthermore, a of apoA-I was secreted in both HepG2 and CaCo-2 as by a of the the removal of apoA-I the glyburide almost completely the formation of endogenously secreted α-LpA-I in both HepG2 and CaCo-2 cells but not preβ1-LpA-I particles secreted by HepG2 cells not we that glyburide had on apoA-I gene in both HepG2 and CaCo-2, as by not To the between the of α-LpA-I particles and fibroblasts were with or as in and and with apoA-I for at ABCA1 mutant cells were as a control in the present The was with a and both and particles were separated by in the of and apoA-I with particles with an the we have not been to α-LpA-I formation incubation with ABCA1 mutant Interestingly, α-LpA-I subspecies with a molecular of to contain only that α-LpA-I subspecies contain cholesterol and the was whether α-LpA-I is a good substrate for LCAT. fibroblasts were with and with for at The was and and apoA-I was removed both and the and were to form r(HDL) with a specific similar to that of α-LpA-I. of either α-LpA-I or r(HDL) were reacted with human LCAT as in and both and unesterified cholesterol were separated by The initial in with than substrate to in which the substrate is between the Vmax of the LCAT between α-LpA-I and r(HDL) vs. nmol LCAT, contrast, of a from of initial as a of substrate for both α-LpA-I and r(HDL) that the Km was 2-fold for α-LpA-I than for r(HDL) (1.2 vs. 0.7 Furthermore, the of LCAT was 2-fold for α-LpA-I compared with r(HDL) vs. nmol apoA-I). esterification was with α-LpA-I mutant compared with α-LpA-I vs. we found that incubation of apoA-I with fibroblasts generated α-LpA-I particles similar to with which both and as by not are of results from or HDL is believed to be a against atherosclerotic vascular A of the molecular basis for these mechanisms be for for the and of atherosclerotic vascular Although it has generally that this of HDL is to its role in the RCT the structural basis for the and of HDL particles complex and not well understood. It is generally thought that the interaction of apoA-I with from cell membranes generates a with preβ mobility that cholesterol from cells S. of free apolipoproteins with of density lipoproteins and of cellular cholesterol.J. Biol. Chem. Scholar, density of apolipoprotein A-I to Scholar). Here, we present evidence that incubation of apoA-I with cell including human fibroblasts, CaCo-2, and generates only α-LpA-I. contrast, apoA-I was unable to form such particles in the of and ABCA1 mutant cells with studies that apoA-I not promote cholesterol efflux from endothelial cells in which the of ABCA1 protein is very and not to be to with cholesterol or P.E. K. G. Fielding C.J. A mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein Scholar, M. J. of cholesterol efflux in vascular endothelial Scholar). Furthermore, the role of ABCA1 in the formation of α-LpA-I was supported by our results that an of ABCA1 transporter almost completely the formation of larger α-LpA-I particles in different cell A major in the concept of RCT from the of Brewer and colleagues (12Basso F. Freeman L. Knapper C.L. Remaley A. Stonik J. Neufeld E.B. Tansey T. Amar M.J. Fruchart-Najib J. Duverger N. et al.Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations.J. Lipid Res. 2003; 44: 296-302Google Scholar) that the is a major of plasma and that the of of hepatic ABCA1 intracellular cholesterol levels as well as plasma This concept is supported by our results that HepG2 cells with apoA-I both preβ1-LpA-I and α-LpA-I This was by our that endogenously secreted particles from HepG2 cells were associated with preβ1-LpA-I and α-LpA-I with charge and similar to plasma preβ1-LpA-I and α-LpA-I contrast, CaCo-2 cells secreted only α-LpA-I. Thus, cell lines and macrophages have the to form preβ1-LpA-I. Although the structural for the formation of preβ1-LpA-I by and macrophages have not been studies that the composition of preβ1-LpA-I as well as the of apoA-I these particles from of HDL (6Kawano M. Miida T. Fielding C.J. Fielding P.E. Quantitation of pre beta-HDL-dependent and nonspecific components of the total efflux of cellular cholesterol and phospholipid.Biochemistry. 1993; 32: 5025-5028Google Scholar, C.J. Fielding P.E. Molecular of reverse cholesterol Lipid Res. Scholar). the ABCA1 transporter to be not involved in the formation of with our that 1) glyburide not the formation of preβ1-LpA-I in both HepG2 cells and macrophages and 2) of HepG2 cells with increased the of endogenously secreted but not compared with cells not This is with the that with not have in only have HDL L. Marcil M. J. and functional of human plasma lipoprotein containing only Lipid Res. 2003; 44: Scholar, Eckardstein A. Y. S. G. Assmann G. cholesterol transport in plasma of with different forms of familial HDL Thromb. Vasc. Biol. Scholar). This provides in for the concept that ABCA1 is not involved in the formation of HDL. It is that apoA-I interacts with specific of plasma membranes or present in HepG2 cells and macrophages but not which results in the phospholipid composition of these its preβ electrophoretic These are supported by a study by and colleagues A. G. Y.L. The lipidation by of human apolipoprotein A-I occurs by both ABCA1-dependent and -independent Biol. Chem. 2003; Scholar) demonstrating that of ABCA1 in is to the lipidation of however, a of apoA-I occurs in from Although the mechanism of the lipidation of apoA-I by ABCA1 transporter to be in the present study that of endogenously secreted apoA-I by HepG2 cells was associated with α-LpA-I it is likely that these particles were by the of This is with a study by and colleagues from HepG2 evidence for the of both lipid-poor apoA-I and nascent Lipid Res. 2002; Scholar) demonstrating that of secreted apoA-I from HepG2 cells is and is studies have suggested that preβ-HDL be an P.E. K. G. Fielding C.J. A mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein Scholar, S. of free apolipoproteins with of density lipoproteins and of cellular cholesterol.J. Biol. Chem. Scholar, O.L. Fielding C.J. of human acyltransferase in of human apolipoprotein and human apolipoprotein on plasma lipoprotein cholesterol Clin. Invest. the between particles in our cell was It is that the interaction of apoA-I with ABCA1 generates that may be a for α-LpA-I in our cell However, a that both preβ1-LpA-I and α-LpA-I generated by HepG2 cells or α-LpA-I generated by fibroblasts in the as as into the incubation important in subspecies a incubation Furthermore, the of the molecular and charge of α-LpA-I and preβ1-LpA-I subspecies a incubation not the of a between nascent This is also supported by our results that glyburide not the formation of preβ1-LpA-I but had a on for the concept that preβ1-LpA-I and α-LpA-I have different by and has that apoA-I with cells including cells R.W. extracellular assembly of nascent HDL Lipid Res. 1993; 34: Scholar, L. between nascent particles that are in cell Lipid Res. 1996; Scholar), fibroblasts W.J. of from fibroblasts to on levels of cellular unesterified cholesterol.J. Lipid Res. Scholar), and macrophages S. of free apolipoproteins with of density lipoproteins and of cellular cholesterol.J. Biol. Chem. Scholar, W.J. S. of cellular cholesterol and phospholipid to apolipoproteins and A 34: Scholar) was to phospholipid and cholesterol from the cells to form with distinct that the α-LpA-I in different cell lines had different suggesting that the heterogeneity of particles may be to the the of apoA-I This is with our finding that α-LpA-I subspecies generated by fibroblasts a molecular of only Although the structural characteristics that the electrophoretic mobility of nascent has not been we have suggested that the in M. Marcil M. M. L. J. Molecular and cellular of apolipoprotein A-I lipidation by the cassette transporter Biol. Chem. Scholar) or the of apoA-I M. Marcil M. M. L. J. Characterization of human cassette transporter implications for determining the of nascent density lipoprotein Biol. Chem. Scholar) may the charge of nascent and electrophoretic Moreover, because of the of LCAT in the to unesterified cholesterol to for α-LpA-I generated by fibroblasts, it is likely that α-LpA-I particles are However, our results the concept that the electrophoretic mobility of HDL is to the LCAT P.E. K. G. Fielding C.J. A mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein Scholar, C.J. Fielding P.E. Molecular of reverse cholesterol Lipid Res. Scholar, K.A. P.J. and metabolism of lipid-poor apolipoprotein Thromb. Vasc. Biol. Scholar). Although the of plasma preβ1-LpA-I has and its role in is at this K.A. P.J. and metabolism of lipid-poor apolipoprotein Thromb. Vasc. Biol. Scholar, S. lipoprotein and disease in of the Thromb. Vasc. Biol. Scholar, T. Y. K. T. T. T. M. lipoprotein in Chem. 1996; Scholar), a study by and colleagues L. M.J. density lipoprotein has in human apolipoprotein A-I Lipid Res. Scholar) documented that into human apoA-I has removal from plasma and by or remodeling to HDL, which occurs of both LCAT and Furthermore, it is well that remodeling of HDL by several enzymes, such as hepatic lipase, transfer protein, and phospholipid transfer protein, generates preβ1-LpA-I (3Barter P.J. Hugh Sinclair Lecture. The regulation and remodelling of HDL by plasma factors.Atheroscler. Suppl. 2002; 3: 39-47Google Scholar, K.A. P.J. and metabolism of lipid-poor apolipoprotein Thromb. Vasc. Biol. Scholar). are the phospholipid composition and of preβ1-LpA-I generated by and Although the structural of nascent required to form HDL are as we have evidence that α-LpA-I had different the larger particles both and whereas the particles only and apoA-I in this study have that the of cholesterol esterification by LCAT are similar for α-LpA-I subspecies and r(HDL) contrast, LCAT was found to have a 2-fold for r(HDL) compared with α-LpA-I. This that the that LCAT to α-LpA-I cholesterol is likely to the in of these nascent particles. It is that LCAT was by factors such as phospholipid composition, apoA-I and surface charge of α-LpA-I. Indeed, it was documented that the of apoA-I in and r(HDL) and the LCAT K.A. P.J. The of on the and of reconstituted density Biol. Chem. 1996; Scholar), with our results that a of was found in α-LpA-I generated by fibroblasts M. Marcil M. M. L. J. Molecular and cellular of apolipoprotein A-I lipidation by the cassette transporter Biol. Chem. Scholar). Interestingly, we found that was to α-LpA-I. This that both and LCAT may in for an of nascent particles Although the composition and of nascent to be the present study has evidence for a new link between specific cell lines and the speciation of nascent HDL that occurs by both ABCA1-dependent and -independent pathways. The S. and L. for human lecithin:cholesterol acyltransferase and apoA-I The of is also This was supported by from the of and by the and of the in

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