cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts

ATP-binding cassette transporter A1 (ABC22222222222263) plays a crucial role in apoA-I lipidation, a key step in reverse cholesterol transport. cAMP induces apoA-I binding activity and promotes cellular cholesterol efflux. We investigated the role of the cAMP/protein kinase A (PKA) dependent pathway in the regulation of cellular cholesterol efflux. Treatment of normal fibroblasts with 8-bromo-cAMP (8-Br-cAMP) increased significantly apoA-I-mediated cholesterol efflux, with specificity for apoA-I, but not for cyclodextrin. Concomitantly, 8-Br-cAMP increased ABCA1 phosphorylation in a time-dependent manner. Maximum phosphorylation was reached in <10 min, representing a 260% increase compared to basal ABCA1 phosphorylation level. Forskolin, a known cAMP regulator, increased both cellular cholesterol efflux and ABCA1 phosphorylation. In contrast, H-89 PKA inhibitor reduced cellular cholesterol efflux by 70% in a dose-dependent manner and inhibited almost completely ABCA1 phosphorylation. To determine whether naturally occurring mutants of ABCA1 may affect its phosphorylation activity, fibroblasts from subjects with familial HDL deficiency (FHD, heterozygous ABCA1 defect) and Tangier disease (TD, homozygous/compound heterozygous ABCA1 defect) were treated with 8-Br-cAMP or forskolin. Cellular cholesterol efflux and ABCA1 phosphorylation were increased in FHD but not in TD cells.Taken together, these findings provide evidence for a link between the cAMP/PKA-dependent pathway, ABCA1 phosphorylation, and apoA-I mediated cellular cholesterol efflux. ATP-binding cassette transporter A1 (ABC22222222222263) plays a crucial role in apoA-I lipidation, a key step in reverse cholesterol transport. cAMP induces apoA-I binding activity and promotes cellular cholesterol efflux. We investigated the role of the cAMP/protein kinase A (PKA) dependent pathway in the regulation of cellular cholesterol efflux. Treatment of normal fibroblasts with 8-bromo-cAMP (8-Br-cAMP) increased significantly apoA-I-mediated cholesterol efflux, with specificity for apoA-I, but not for cyclodextrin. Concomitantly, 8-Br-cAMP increased ABCA1 phosphorylation in a time-dependent manner. Maximum phosphorylation was reached in <10 min, representing a 260% increase compared to basal ABCA1 phosphorylation level. Forskolin, a known cAMP regulator, increased both cellular cholesterol efflux and ABCA1 phosphorylation. In contrast, H-89 PKA inhibitor reduced cellular cholesterol efflux by 70% in a dose-dependent manner and inhibited almost completely ABCA1 phosphorylation. To determine whether naturally occurring mutants of ABCA1 may affect its phosphorylation activity, fibroblasts from subjects with familial HDL deficiency (FHD, heterozygous ABCA1 defect) and Tangier disease (TD, homozygous/compound heterozygous ABCA1 defect) were treated with 8-Br-cAMP or forskolin. Cellular cholesterol efflux and ABCA1 phosphorylation were increased in FHD but not in TD cells. Taken together, these findings provide evidence for a link between the cAMP/PKA-dependent pathway, ABCA1 phosphorylation, and apoA-I mediated cellular cholesterol efflux. The importance of ATP-binding cassette transporter A1 (ABCA1) in reverse cholesterol transport (RCT) process has been strikingly demonstrated by the identification of mutations in ABCA1 gene locus as the molecular defect of Tangier disease (TD) and familial HDL deficiency (FHD) (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S. Kastelein J.J. Genest Jr., J. Hayden M.R. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar, 2Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L.H. Yu L. Collins J.A. van Dam M. Molhuizen H.O. Loubster O. Ouellette B.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J. Hayden M.R. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.Lancet. 1999; 354: 1341-1346Google Scholar). Those patients were characterized by extremely low HDL levels caused by inadequate transport of cellular cholesterol and phospholipids to the extracellular space, leading to hypercatabolism of lipid-poor nascent HDL particles (3Batal R. Tremblay M. Krimbou L. Mamer O. Davignon J. Genest Jr., J. Cohn J.S. Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 655-664Google Scholar). Thus, factors affecting the structure, activity, or concentration of ABCA1 are likely to affect the homeostasis of plasma HDL cholesterol and the RCT process, one of several proposed mechanisms (4Tall A.R. Plasma cholesteryl ester transfer protein.J. Lipid Res. 1993; 34: 1255-1274Google Scholar) by which HDL may protect against atherosclerosis. ABCA1 is a 240 kDa protein belonging to a large family of conserved transmembrane proteins that transport a wide variety of substrates, including ions, drugs, peptides, and lipid across cell membranes (5Croop J.M. Evolutionary relationships among ABC transporters.Methods Enzymol. 1998; 292: 101-116Google Scholar). ABC transporters have been associated with many diseases such as drug-resistant cancer (6Tusnady G.E. Bakos E. Varadi A. Sarkadi B. Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters.FEBS Lett. 1997; 402: 1-3Google Scholar), diabetes (7Thomas P.M. Cote G.J. Wohllk N. Haddad B. Mathew P.M. Rabl W. Aguilar-Bryan L. Gagel R.F. Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.Science. 1995; 268: 426-429Google Scholar), and cystic fibrosis (8Strautnieks S.S. Bull L.N. Knisely A.S. Kocoshis S.A. Dahl N. Arnell H. Sokal E. Dahan K. Childs S. Ling V. Tanner M.S. Kagalwalla A.F. Nemeth A. Pawlowska J. Baker A. Meili-Vergani G. Freimer N.B. Gardiner R.M. Thompson R.J. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.Nat. Genet. 1998; 20: 233-238Google Scholar), making these proteins potential targets for therapeutic intervention (9Demolombe S. Escande D. ATP-binding cassette proteins as targets for drug discovery.Trends Pharmacol. Sci. 1996; 17: 273-275Google Scholar). The ABCA1 gene product is a member of the superfamily of ATP binding cassette transporters predicted to contain 12 transmembrane spanning domains and two nucleotide binding folds (NBF) responsible for the degradation of ATP to provide the energy required for the transport activity (10Dean M. Allikmets R. Evolution of ATP-binding cassette transporter genes.Curr. Opin. Genet. Dev. 1995; 5: 779-785Google Scholar). The NBF domains contain the highly conserved phosphate-binding loop (11Walker J.E. Saraste M. Runswick M.J. Gay N.J. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.EMBO J. 1982; 1: 945-951Google Scholar) that forms intimate contacts with the β- and γ-phosphates of bound ATP (12Saraste M. Sibbald P.R. Wittinghofer A. The P-loop—a common motif in ATP- and GTP-binding proteins.Trends Biochem. Sci. 1990; 15: 430-434Google Scholar). In some cases, evidence has been provided for a further regulation via phosphorylation of serine/threonine residues in the NBF region (13Picciotto M.R. Cohn J.A. Bertuzzi G. Greengard P. Nairn A.C. Phosphorylation of the cystic fibrosis transmembrane conductance regulator.J. Biol. Chem. 1992; 267: 12742-12752Google Scholar). The interaction between apoA-I and ABCA1 is of critical importance for the active apoA-I lipidation, but the structural and functional pathways involved in this process have not been established. Of interest, the earlier attractive concept of Smith et al. (14Smith J.D. Miyata M. Ginsberg M. Grigaux C. Shmookler E. Plump A.S. Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors.J. Biol. Chem. 1996; 271: 30647-30655Google Scholar) suggested that cAMP induces a membrane apolipoprotein receptor that does not lead to endocytosis and degradation, but instead promotes the transfer of lipids to apolipoprotein. The same group had also reported later that cAMP-mediated cholesterol efflux to apoA-I is associated with the binding, uptake, and resecretion of apoA-I in a calcium-dependent pathway in murine macrophages (15Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Google Scholar). The effect of cAMP on ABCA1 mRNA and protein appears to be specific to macrophages and is not seen with a number of other cell types (16Bortnick A.E. Rothblat G.H. Stoudt G. Hoppe K.L. Royer L.J. McNeish J. Francone O.L. The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines.J. Biol. Chem. 2000; 275: 28634-28640Google Scholar). Moreover, it has been documented that cAMP induces apoA-I binding activity and promotes cellular cholesterol efflux via ABCA1 protein in macrophages (17Oram J.F. Lawn R.M. Garvin M.R. Wade D.P. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages.J. Biol. Chem. 2000; 275: 34508-34511Google Scholar). On the other hand, treatment of immortalized fibroblasts with cAMP analog also induces apoA-I-mediated lipid efflux and ABCA1 expression, but these effects are usually modest and require some cholesterol loading of cells (18Lawn R.M. Wade D.P. Garvin M.R. Wang X. Schwartz K. Porter J.G. Seilhamer J.J. Vaughan A.M. Oram J.F. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway.J. Clin. Invest. 1999; 104: R25-R31Google Scholar, 19Oram J.F. Mendez A.J. Lymp J. Kavanagh T.J. Halbert C.L. Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells.J. Lipid Res. 1999; 40: 1769-1781Google Scholar). We have previously shown that phospholipid breakdown products, mediated by phospholipase C and D, and the activation of protein kinase C modulate cellular cholesterol efflux (20Haidar B. Mott S. Boucher B. Lee C.Y. Marcil M. Genest Jr., J. Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts.J. Lipid Res. 2001; 42: 249-257Google Scholar). The involvement of apoA-I in cellular signaling processes and its property to induce cellular cholesterol efflux via its interaction with ABCA1 led us to hypothesize that cAMP/protein kinase A (PKA)-dependent pathway may modulate cellular cholesterol efflux via activation of ABCA1 by inducing its phosphorylation. The present study aims to provide evidence for links between apoA-I-mediated cellular cholesterol efflux, cAMP, PKA, and ABCA1 phosphorylation, and to examine how these interactions could be affected by cAMP regulators, PKA inhibitors, or naturally occurring mutants of ABCA1 protein. Patients with FHD and TD were selected as previously described (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L.H. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O. Loubser O. Ouelette B.F. Fichter K. Ashbourne-Excoffon K.J. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S. Kastelein J.J. Genest Jr., J. Hayden M.R. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar, 2Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L.H. Yu L. Collins J.A. van Dam M. Molhuizen H.O. Loubster O. Ouellette B.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J. Hayden M.R. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.Lancet. 1999; 354: 1341-1346Google Scholar, 21Marcil M. Yu L. Krimbou L. Boucher B. Oram J.F. Cohn J.S. Genest Jr., J. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 159-169Google Scholar, 22Marcil M. Boucher B. Krimbou L. Solymoss B.C. Davignon J. Frohlich J. Genest Jr., J. Severe familial HDL deficiency in French-Canadian kindreds. Clinical, biochemical, and molecular characterization.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1015-1024Google Scholar). All these subjects carry a mutation at the ABCA1 gene locus or had clinical signs of TD. For the present study, we selected fibroblasts from two normal subjects patients with FHD and patients with TD Cellular in TD subjects a of apoA-I-mediated cellular cholesterol efflux. of the ABCA1 gene a heterozygous for subjects and and a mutation in The for the study was and by the of the forms for and were fibroblasts were from of the of patients and subjects and were as described M. Yu L. Krimbou L. Boucher B. Oram J.F. Cohn J.S. Genest Jr., J. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 159-169Google Scholar). We cells in cell in with and or 1 was in the cell the cells reached were in 1 of and the was by and of lipoprotein cholesterol for Cellular cholesterol were to for in 1 were in 1 and apoA-I in the or of efflux signaling cholesterol efflux was on the cell as was in the efflux All were in and efflux was at In some cells were treated with 8-bromo-cAMP (8-Br-cAMP) as described previously J.F. Mendez A.J. Lymp J. Kavanagh T.J. Halbert C.L. Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells.J. Lipid Res. 1999; 40: 1769-1781Google Scholar) with the cells 8-Br-cAMP and efflux the cells were on and the was To the was for at The cell was in at Cellular protein concentration was by the O. N.J. R.J. with the Biol. Chem. Scholar) and one was for of cellular Cellular cholesterol efflux was as in in in the were as of The of cholesteryl ester was by fibroblasts were with for with cholesterol for at as described by and 8-Br-cAMP were to the with 1 of at the cells were with and for both lipids and lipids were with at for min, by a with of in the was with of for at and by Lipid were in of and cholesterol and cholesteryl ester were from other lipids as the and with The and were and was by HDL was from plasma of a with with The HDL was in and proteins were at on two in the apoA-I were in and in at concentration of 1 was by on apoA-I and were in and at as A for human ABCA1 and ABCA1 were by reverse on from normal human and from was by a step the and the reverse The was and to to the of the product with and the was from and the The was at concentration of in to of the cell were on a and to a membrane for were on a fibroblasts were with cholesterol for in and with of for at The cells were in and treated or not with 1 8-Br-cAMP for of as in were also treated with as for the the cells were with and of and and the was to for at in of a inhibitor Cellular were by at for at was by protein to the from as was of cellular by with of a of and for on a at proteins were by at for 1 The cell was at with of to the of residues of the human ABCA1 gene of of the cell was for were at for 1 min, and with and for in a and The were by at for were by and to membrane at representing ABCA1 were on a For protein loading the same membranes were with and with for 1 at were at with ABCA1 in and with for at were for 1 at with in and with for were by for In the present study, we that treatment of normal fibroblasts with 8-Br-cAMP increased apoA-I-mediated cellular efflux by and at and as shown in We also a increase in apoA-I-mediated phospholipid efflux in the of 8-Br-cAMP not To determine whether this effect of cAMP is not to of cellular we the cellular cholesterol efflux 1 We that 8-Br-cAMP not affect cholesterol efflux, as shown in were to the specificity of apoA-I and 8-Br-cAMP We that of and a inhibitor known to be a cAMP regulator, were as as 8-Br-cAMP in apoA-I-mediated cellular cholesterol efflux in normal cells The effect of 8-Br-cAMP on cellular cholesterol efflux was shown to be and was on these cellular cholesterol efflux were at We in normal cells whether the increase in apoA-I-mediated cholesterol efflux by 8-Br-cAMP was associated with in cellular ABCA1 fibroblasts were for with 8-Br-cAMP was effect of cAMP on ABCA1 mRNA levels in fibroblasts 8-Br-cAMP increased ABCA1 mRNA in macrophages as in this that cAMP could cholesteryl ester activity in some cell types A. Rothblat G.H. J.M. cAMP cholesteryl ester to in macrophages.J. Biol. Chem. Scholar). In to the that apoA-I-mediated cellular cholesterol efflux by 8-Br-cAMP was not dependent on increased and cholesterol normal fibroblasts were and as described in 8-Br-cAMP and were at as by the of was to the of the Cellular was at by The of 8-Br-cAMP had effect on the of cholesterol In to the of cAMP/PKA-dependent pathway with ABCA1 phosphorylation activity, ABCA1 was in cells and with as described in The specificity of was by of which a molecular of and was by both and not The phosphorylation of ABCA1 was investigated by treatment of normal cells with 8-Br-cAMP for of and cells were as for of ABCA1 was and by were to ABCA1 was by and the same membrane was for ABCA1 protein by as described in shown in treatment of normal fibroblasts with 8-Br-cAMP increased ABCA1 phosphorylation in a time-dependent manner. Maximum phosphorylation was reached in min, representing a 260% increase compared to basal phosphorylation of ABCA1 in and for the of the ABCA1 was by increase of from from the same cell is of is shown in the of In to provide evidence for a specific role of PKA in apoA-I-mediated cellular cholesterol efflux process and ABCA1 phosphorylation activity, we the effect of H-89 PKA inhibitor on cellular cholesterol efflux and ABCA1 phosphorylation. Treatment of normal cells with H-89 significantly basal apoA-I-mediated cholesterol efflux in the of 8-Br-cAMP also basal ABCA1 phosphorylation not In H-89 reduced cellular cholesterol efflux by 70% in a dose-dependent manner in the of 1 8-Br-cAMP On the other hand, H-89 almost completely in a dependent manner ABCA1 phosphorylation a to as shown in the of we that of the serine/threonine by increased the phosphorylation of ABCA1 in normal cells not To determine whether naturally occurring mutants of ABCA1 may affect cellular cholesterol efflux and ABCA1 phosphorylation activity, fibroblasts from subjects with FHD and TD were treated with 8-Br-cAMP or Cellular cholesterol efflux was increased in but not in TD cells to 8-Br-cAMP cells from a normal FHD and TD subjects were with in the or of 8-Br-cAMP shown in ABCA1 phosphorylation was increased in and FHD cells compared to basal phosphorylation levels in the of the same ABCA1 from cells further phosphorylation The was to the 8-Br-cAMP We demonstrated that was as as 8-Br-cAMP in inducing ABCA1 phosphorylation in and but not in TD cells of ABCA1 gene in study of the are heterozygous for the reported are heterozygous and is not in a are heterozygous for the reported are heterozygous and is not cAMP has been to apoA-I-mediated cellular lipid efflux (14Smith J.D. Miyata M. Ginsberg M. Grigaux C. Shmookler E. Plump A.S. Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors.J. Biol. Chem. 1996; 271: 30647-30655Google Scholar). we have shown that 8-Br-cAMP increased apoA-I-mediated cellular cholesterol efflux in normal but not affect cholesterol efflux the same treatment of normal cells with 8-Br-cAMP increased ABCA1 phosphorylation in a time-dependent manner. min, a increase in ABCA1 phosphorylation was compared to the basal phosphorylation in cells The effect of 8-Br-cAMP on cellular cholesterol efflux and ABCA1 phosphorylation was not to increased ABCA1 mRNA and increased protein levels have documented that both ABCA1 mRNA and protein levels are by cAMP treatment in macrophages (16Bortnick A.E. Rothblat G.H. Stoudt G. Hoppe K.L. Royer L.J. McNeish J. Francone O.L. The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines.J. Biol. Chem. 2000; 275: 28634-28640Google Scholar, J.F. Lawn R.M. Garvin M.R. Wade D.P. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages.J. Biol. Chem. 2000; 275: 34508-34511Google Scholar). 8-Br-cAMP not affect the activity of cholesteryl ester is likely that a signaling pathway induces or key proteins involved in the apolipoprotein-mediated lipid removal The effects of 8-Br-cAMP on cellular cholesterol efflux and ABCA1 phosphorylation were by that known as of induces both increased cellular cholesterol efflux and ABCA1 phosphorylation in normal cells and are with the concept that a cAMP/PKA-dependent pathway may cellular cholesterol efflux. concept is further by the H-89 PKA inhibitor significantly cellular cholesterol efflux and ABCA1 phosphorylation was also reduced by H-89 evidence for the link between ABCA1 phosphorylation and cellular cholesterol efflux was provided by the that increase in apoA-I-mediated cholesterol efflux was the of treatment with 8-Br-cAMP with the of phosphorylation of ABCA1 in of 8-Br-cAMP Of interest, it has been demonstrated that induces kinase phosphorylation in cells via cAMP/PKA-dependent pathway M. Y. K. G. S. N. E pathway in in Res. 292: Scholar), and apoA-I human by activation of kinase Y. S. human by activation of 1998; Scholar). that may cAMP which was determine by the of cellular and 1992; Scholar) that lead to the activation of PKA and activation of ABCA1 by its phosphorylation. be of to determine whether apoA-I mutations affecting its and residues in the cAMP/PKA-dependent pathway and ABCA1 phosphorylation the structural of ABCA1 activation and its interaction with apoA-I has not been the present study that fibroblasts from TD patients were to increase apoA-I cholesterol efflux and ABCA1 protein phosphorylation by 8-Br-cAMP or treatment 8-Br-cAMP or increased both cellular cholesterol efflux and ABCA1 phosphorylation in normal and FHD cells. has been demonstrated that apoA-I to increased apoA-I binding N. P. A.R. binding of cholesterol efflux, and plasma membrane in cells Biol. Chem. 2000; 275: Scholar). The binding of apoA-I to fibroblasts from TD patients has been reported to be abnormal Oram J.F. removal of cellular cholesterol and phospholipids by apolipoprotein in Tangier Clin. Invest. 1995; 96: Scholar), but not in FHD patients M. Yu L. Krimbou L. Boucher B. Oram J.F. Cohn J.S. Genest Jr., J. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 159-169Google Scholar). In the present study, we cell from a FHD with heterozygous mutation in and a TD with for a defect in and a mutation in from the study of these patients suggested that specific mutations in ABCA1 could affect its interaction with apoA-I molecules and its phosphorylation. abnormal of ABCA1 in TD cells may affect the serine/threonine phosphorylation was reported that a mutation of protein and of specificity and in of transport activity of other and had effect K. C. of in the protein specificity and in of transport Biol. Chem. 2001; Scholar). In phosphorylation of ABC transporter was proposed to role in its activity S.M. M.J. of the cystic fibrosis transmembrane conductance by specific protein kinases and protein Biol. Chem. 1993; 268: Scholar). The interaction between apoA-I and ABCA1 is by by et al. J.S. Mendez A.J. occurring mutations in extracellular its interaction with apolipoprotein Biol. Chem. Scholar) that apoA-I cholesterol efflux interaction between apolipoprotein and critical residues in two extracellular of ABCA1 protein. Cellular cholesterol efflux appears to be of plasma is on the that ABCA1 lead to a deficiency of plasma and cellular cholesterol efflux with plasma S.M. Kastelein J.J. van Dam M. Marcil M. Roomp K. Collins J.A. R. N. R. Boucher B. C. C. Brooks-Wilson A. Molhuizen H.O. Frohlich J. Genest Jr., J. Hayden M.R. and cholesterol efflux affect HDL cholesterol levels and disease in ABCA1 Clin. Invest. 2000; Scholar). The regulation of cellular cholesterol efflux is and is both at the and levels in cells. be to increase ABCA1 mRNA levels in cells such as fibroblasts in to increase cellular cholesterol efflux. the of both the of ABCA1 protein and its activation by phosphorylation have potential as therapeutic at levels in plasma of patients at increased for The in this study provide evidence that apoA-I with cAMP/PKA-dependent pathway leading to ABCA1 phosphorylation. process in a key functional role in the activation of ABCA1 by its phosphorylation, cholesterol to study of the role of apoA-I in cellular signaling and its interaction with ABCA1 protein may provide the of reverse cholesterol plasma factors affecting HDL and the therapeutic potential of ABCA1 in or was by from the of and from the and was provided by as of the J.G. is the of the in at We D. for ATP-binding cassette transporter A1 cholesteryl ester normal cholesterol familial HDL deficiency nucleotide binding folds protein kinase A Tangier disease 8-bromo-cAMP

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