Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL

HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL. HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL. The principal antiatherogenic function of HDL is its ability to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion, process termed reverse cholesterol transport (RCT) (1.Stein O. Stein Y. Atheroprotective mechanisms of HDL.Atherosclerosis. 1999; 144: 285-301Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). This concept was further confirmed once a homozygous defect in ABCA1 [Mendelian Inheritance in Man (MIM) 205400 and 600046] was discovered to cause Tangier disease, a condition characterized by a virtual absence of HDL in plasma and a resultant accumulation of cholesteryl esters within cells (2.Bodzioch M. Orso E. Klucken J. Langmann T. Bottcher A. Diederich W. Drobnik W. Barlage S. Buchler C. Porsch-Ozcurumez M. et al.The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.Nat. Genet. 1999; 22: 347-351Crossref PubMed Scopus (1338) Google Scholar, 3.Brooks-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. 1999; 22: 336-345Crossref PubMed Scopus (1494) Google Scholar, 4.Rust S. Rosier M. Funke H. Real J. Amoura Z. Piette J. Deleuze J. Brewer H. Duverger N. Denefle P. et al.Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.Nat. Genet. 1999; 22: 352-355Crossref PubMed Scopus (1258) Google Scholar). The ABCA1 protein mediates the efflux of phospholipids and unesterified cholesterol from peripheral cells to HDL. A lipid-poor apolipoprotein A-I (apoA-I)-phospholipid complex, the preβ-HDL particle, is the most effective cholesterol acceptor in ABCA1-mediated efflux (5.Brewer Jr., H.B. Remaley A.T. Neufeld E.B. Basso F. Joyce C. Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1755-1760Crossref PubMed Scopus (148) Google Scholar). The activity of ABCA1 in the liver is the major contributor to the generation of HDL, accounting for ∼80% of the circulating HDL reserve (6.Timmins J.M. Lee J.Y. Boudyguina E. Kluckman K.D. Brunham L.R. Mulya A. Gebre A.K. Coutinho J.M. Colvin P.L. Smith T.L. et al.Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I.J. Clin. Invest. 2005; 115: 1333-1342Crossref PubMed Scopus (420) Google Scholar, 7.Brunham L.R. Kruit J.K. Iqbal J. Fievet C. Timmins J.M. Pape T.D. Coburn B.A. Bissada N. Staels B. Groen A.K. et al.Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.J. Clin. Invest. 2006; 116: 1052-1062Crossref PubMed Scopus (417) Google Scholar). Based on these estimations of the contribution of liver and intestine to the HDL plasma pool, it can be stated that the monocyte/macrophage ABCA1 only minimally affects plasma HDL levels (8.Haghpassand M. Bourassa P.A. Francone O.L. Aiello R.J. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels.J. Clin. Invest. 2001; 108: 1315-1320Crossref PubMed Scopus (232) Google Scholar). Therefore, hepatic ABCA1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of lipid-poor apoA-I, as it slows the HDL catabolism in the kidney and prolongs its residence time in plasma. In subjects heterozygous for a defective allele of the ABCA1 gene, cholesterol efflux is decreased to approximately half of that in normal individuals (9.Clee S.M. Kastelein J.J. Dam M.van Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. et al.Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.J. Clin. Invest. 2000; 106: 1263-1270Crossref PubMed Scopus (285) Google Scholar, 10.Brousseau M.E. Eberhart G.P. Dupuis J. Asztalos B.F. Goldkamp A.L. Schaefer E.J. Freeman M.W. Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size.J. Lipid Res. 2000; 41: 1125-1135Abstract Full Text Full Text PDF PubMed Google Scholar). The heterozygotes also have increased carotid artery intima-media thickness (IMT) and low high density lipoprotein-cholesterol (HDL-C) and thus are at increased risk for the development of early atherosclerosis (11.van Dam M.J. Groot E.de Clee S.M. Hovingh G.K. Roelants R. Brooks-Wilson A. Zwinderman A.H. Smit A.J. Smelt A.H. Groen A.K. et al.Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.Lancet. 2002; 359: 37-42Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). The association between ABCA1 variants and HDL-C levels was initially reported in French-Canadian families with familial hypoalphalipoproteinemia (3.Brooks-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. 1999; 22: 336-345Crossref PubMed Scopus (1494) Google Scholar) and subsequently in Dutch, North American, and Danish study cohorts (9.Clee S.M. Kastelein J.J. Dam M.van Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. et al.Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.J. Clin. Invest. 2000; 106: 1263-1270Crossref PubMed Scopus (285) Google Scholar, 12.Wang J. Burnett J.R. Near S. Young K. Zinman B. Hanley A.J. Connelly P.W. Harris S.B. Hegele R.A. Common and rare ABCA1 variants affecting plasma HDL cholesterol.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1983-1989Crossref PubMed Scopus (113) Google Scholar, 13.Hong S.H. Rhyne J. Zeller K. Miller M. ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease.Atherosclerosis. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, R. A. in transporter contributes to HDL cholesterol in the Clin. Invest. 2004; PubMed Scopus Google Scholar). it was that to of in the HDL-C are heterozygous for rare mutations in ABCA1 R. A. in transporter contributes to HDL cholesterol in the Clin. Invest. 2004; PubMed Scopus Google Scholar). However, also of the of association between ABCA1 variants and the of HDL-C M.E. M. Schaefer E.J. Goldkamp A.L. M. J.M. C. et variants in the gene encoding ATP-binding cassette transporter 1 in with low HDL cholesterol levels and coronary heart disease.Atherosclerosis. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. M. M.E. M.J. ATP-binding cassette transporter is not a major of HDL-C levels in a at high risk for coronary heart disease.Atherosclerosis. Full Text Full Text PDF PubMed Scopus Google Scholar, A. P. K. T. M. L. for on and in J. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In to macrophages also as ABCG1 H. C. A. 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The of patients with low levels of HDL-C be the of decreased cholesterol efflux from peripheral cells to HDL, a defect of HDL as a cholesterol a of We the of cholesterol efflux using as a monocyte-derived macrophages from subjects with familial low HDL and increased risk for premature coronary heart disease We that subjects with familial low HDL have reduced cholesterol efflux via ABCA1 and risk alleles of the ABCA1 gene to the in be at the transcript as an expression of ABCA1 cholesterol and The levels of ABCG1 mRNA expression were also measured to whether the transcript levels of the cholesterol transporter suggest a study from characterized low-HDL A. P. K. T. M. L. for on and in J. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and a control healthy and with The low-HDL families were on HDL-C the for and for in at first as in A. P. K. T. M. L. for on and in J. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in the The of the the study and were in with the The study efflux were using cells derived from 22 low-HDL subjects and 21 control subjects. The and of the study in the efflux study are in 1 of single-nucleotide using the was in individuals in the efflux with low HDL were were and control subjects were The and of the individuals are in and of the low-HDL subjects and = = with for particle activity activity apolipoprotein cholesteryl high density intima-media are as with for in a apolipoprotein cholesteryl high density intima-media are as levels of and were measured by as A. P. K. T. M. L. for on and in J. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. C. of low HDL levels in familial Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). was by R. P. M. P. S. F. A. plasma protein the antiatherogenic potential of high density in Thromb. Vasc. 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However, the carriers lower HDL-C = and increased ABCA1 expression = This study is the first of the cholesterol efflux in patients with familial low not Tangier The cholesterol efflux was measured in a cholesterol of macrophages from the study subjects and of cells by with lipid-free apoA-I as a cholesterol We that macrophages derived from low-HDL subjects cholesterol efflux as from the control subjects. However, cholesterol efflux estimated as efflux to the levels of ABCA1 was reduced low-HDL subjects markedly increased the was not associated with decreased cholesterol This be to the of subjects in the cholesterol efflux The efflux that we to cholesterol efflux to apoA-I has S. Remaley A.T. B. E. A. M. Duverger N. et and cholesterol removal from cells of the ABCA1 2001; PubMed Scopus Google Scholar, E. L. S. A.L. M. C. S. E. et cholesterol and in Res. 2005; PubMed Scopus Google Scholar). different can be to the of cholesterol efflux from cells to In of the most were cholesterol efflux to apoA-I as efflux and cholesterol efflux to apoA-I as the of to to protein cholesterol efflux as a not between the low-HDL subjects and the control was a for reduced efflux (P = the low-HDL subjects when the efflux were to the This be to of with and the of individuals to the of the we the of ABCA1 transcript of the macrophages and significantly expression levels in the cells derived from low-HDL subjects. the efflux between the we efflux a for the to ABCA1 transcript and that cells from the low-HDL subjects reduced efflux of cholesterol with the control subjects. The be to it is that the transcript levels not with the ABCA1 protein is an of ABCA1 activity S. of high density lipoprotein by the 2005; PubMed Scopus Google Scholar). the ABCA1 protein in the low-HDL subjects be the observed in mRNA expression a caused by a of the the observed transcript of ABCA1 a defective efflux in ABCA1 variants in the macrophages of low-HDL The mRNA expression levels of ABCG1 in macrophages cholesterol efflux were not significantly different between low-HDL subjects and control subjects. However, as observed with the expression of ABCG1 was in the cells and decreased significantly cholesterol also the of cholesterol and on Langmann T. in control ABCA1 2005; PubMed Scopus Google Scholar). has that the most effective acceptor of cholesterol is the HDL, and not the lipid-poor apoA-I preβ-HDL N. W. F. ATP-binding cassette and cholesterol efflux to high-density 2004; PubMed Scopus Google Scholar, ABCG1 cholesterol to by high density lipoprotein but not by Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). This the early that individuals with high levels of particles are from atherosclerosis E.J. J.J. A.J. J.A. of lipoprotein as measured by to coronary artery disease.Arterioscler. Thromb. Vasc. Biol. PubMed Scopus (285) Google Scholar, B.F. M. J.R. Schaefer E.J. of HDL in patients with coronary heart disease.Arterioscler. Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar). In with a of the absence of protein causes an accumulation of and phospholipids in macrophages and K. A. P. J. Francone O.L. P.A. ABCG1 has a critical role in cholesterol efflux to HDL and 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The ABCG1 gene is on A. J. N. P.A. of the ABCG1 liver an that a novel transcript encoding an of the Biol. 2001; Full Text Full Text PDF PubMed Scopus Google and to variants have However, to heterozygous homozygous in the ABCG1 gene have In that ABCG1 is in macrophages from Tangier patients with control macrophages S. M. C. R. B. M. J. J. P. of the ATP-binding cassette transporter gene ABCG1 in Tangier Res. 2001; PubMed Scopus Google Scholar). the of the ABCA1 gene, we observed that low-HDL subjects rare ABCA1 alleles significantly more often control subjects. in allele between the low-HDL and control A study in a of families with premature and low HDL-C reported of the ABCA1 on HDL-C levels S. J. M. M.E. M.J. ATP-binding cassette transporter is not a major of HDL-C levels in a at high risk for coronary heart disease.Atherosclerosis. Full Text Full Text PDF PubMed Scopus Google Scholar). for the ABCA1 variants were also reported in the HDL and the M.E. M. Schaefer E.J. Goldkamp A.L. M. J.M. C. et variants in the gene encoding ATP-binding cassette transporter 1 in with low HDL cholesterol levels and coronary heart disease.Atherosclerosis. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In in healthy subjects and patients of and French-Canadian the variant was associated with increased levels of HDL, decreased and reduced of atherosclerosis S.M. Zwinderman A.H. Zwarts K.Y. Molhuizen H.O. Roomp K. M.van Dam M.van et in ABCA1 is associated with lipoprotein levels and a risk for coronary artery 2001; PubMed Scopus Google Scholar, S. S. Rosier M. Duverger N. O. S. F. et of ABCA1 gene in to plasma levels and Thromb. Vasc. Biol. 2004; 24: PubMed Scopus Google Scholar). In a a of ABCA1 in a Danish that of the subjects in the of HDL-C are heterozygous for ABCA1 mutations and that ABCA1 in to HDL-C at the R. A. in transporter contributes to HDL cholesterol in the Clin. Invest. 2004; PubMed Scopus Google Scholar). In we of the reported in the Danish of were associated with HDL-C levels results in association with increased The variant showed association with low HDL levels but not with the cholesterol efflux in study the L158 polymorphism with a it is in to be the ABCA1 not with cholesterol efflux but to HDL it be for the of thus it not with the of cholesterol A of study be the of subjects for the cholesterol efflux the The of cells for the efflux and ABCA1 mRNA is of the ABCA1 gene carriers of rare variants in a study but as in these low-HDL families to rare we are that on the in of on the protein is a in to transcript levels of are to the between cholesterol efflux and the levels of in low-HDL subjects. of transporter protein levels be with the development of an be for In on we that macrophages derived from subjects with familial low HDL but decreased cholesterol efflux to apoA-I via the ABCA1 familial low HDL in these families is not caused by rare mutations in the variants are associated with HDL-C as by the contribution of the the in these and ABCA1 mRNA expression in cholesterol-loaded macrophages was increased significantly in the low-HDL group. We that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process in low-HDL subjects. The the and the control subjects for in and are for was from the of the the the the the and the The is by the and has and from and and with

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