Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1

ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 × 108 to 1.5 × 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 × 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice.Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels. ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 × 108 to 1.5 × 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 × 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels. ATP binding cassette transporter A1 (ABCA1) is essential for the transfer of phospholipid (PL) and cholesterol to lipid-free apolipoprotein A-I (apoA-I) to form pre-β-HDL (1Hayden M.R. Clee S.M. Brooks-Wilson A. Genest Jr., J. Attie A. Kastelein J.J.P. Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency.Curr. Opin. Lipidol. 2000; 11: 117-122Crossref PubMed Scopus (109) Google Scholar, 2Schmitz G. Langmann T. Structure, function and regulation of the ABC1 gene product.Curr. Opin. Lipidol. 2001; 12: 129-140Crossref PubMed Scopus (185) Google Scholar, 3Wang N. Silver D.L. Theile C. Tall A.R. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein.J. Biol. Chem. 2001; 276: 23742-23747Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). This is the first step in reverse cholesterol transport (RCT), whereby excess cholesterol is removed from cells and transported as HDL to the liver for eventual excretion in bile (4Glomset J.A. The plasma lecithin:cholesterol acyltransferase reaction.J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar, 5Fielding C.J. Fielding P.E. Intracellular cholesterol transport.J. Lipid Res. 1997; 38: 1503-1521Abstract Full Text PDF PubMed Google Scholar, 6Fielding C.J. Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar, 7Rothblat G.H. de la Llera-Moya M. Atger V. Kellner-Weibel G. Williams D.L. Phillips M.C. Cell cholesterol efflux: integration of old and new observations provides new insights.J. Lipid Res. 1999; 40: 781-796Abstract Full Text Full Text PDF PubMed Google Scholar, 8Tall A.R. Wang N. Mucksavage P. Is it time to modify the reverse cholesterol transport model?.J. Clin. Invest. 2001; 108: 1273-1275Crossref PubMed Scopus (69) Google Scholar). Absence of ABCA1 activity results in Tangier disease, which is characterized by a nearly complete loss of circulating HDL, an accumulation of cholesterol ester (particularly in cells of the reticuloendothelial system), and an increased risk of coronary artery disease (9Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Crossref PubMed Scopus (1509) Google Scholar, 10Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L. Yu L. Collins J.A. van Dam M. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J.P. Hayden M.R. Mutations in the ABC1 gene in familial HDL with cholesterol 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Langmann T. A. S. C. M. K. G. C. G. The gene ATP-binding cassette transporter is in Tangier Genet. 1999; 22: PubMed Scopus Google Scholar, S. M. Brewer Jr., N. P. G. Tangier is by in the gene ATP-binding cassette transporter Genet. 1999; 22: PubMed Scopus Google Scholar, M.R. Wang K. The Tangier disease gene ABC1 the lipid Clin. Invest. 1999; PubMed Scopus Google Scholar, S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Collins J.A. N. T. T. Boucher B. C. C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in for ABCA1 by cholesterol efflux levels and by Clin. Invest. 2000; PubMed Scopus Google Scholar). the of a HDL levels and coronary artery disease, the of HDL a of The that ABCA1 is essential for HDL a to in The of that the of plasma HDL from (4Glomset J.A. The plasma lecithin:cholesterol acyltransferase reaction.J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar, 5Fielding C.J. Fielding P.E. Intracellular cholesterol transport.J. Lipid Res. 1997; 38: 1503-1521Abstract Full Text PDF PubMed Google Scholar, 6Fielding C.J. Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar, 7Rothblat G.H. de la Llera-Moya M. Atger V. Kellner-Weibel G. Williams D.L. Phillips M.C. Cell cholesterol efflux: integration of old and new observations provides new insights.J. Lipid Res. 1999; 40: 781-796Abstract Full Text Full Text PDF PubMed Google Scholar, 8Tall A.R. Wang N. Mucksavage P. Is it time to modify the reverse cholesterol transport model?.J. Clin. Invest. 2001; 108: 1273-1275Crossref PubMed Scopus (69) Google Scholar). ABCA1 is expressed in the liver with that in A. A. N. Zhang O. Hayden M.R. ABCA1 and and levels of Invest. PubMed Scopus Google Scholar, of human ATP-binding cassette transporter in normal and Biol. 2001; PubMed Scopus Google suggesting that may may play a major role in HDL This is by the that the of the accumulation of ester in the a of ABCA1 Brooks-Wilson A. V. A. Zhang Kastelein G. Hayden M.R. and of a in the ABCA1 gene of the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of mice with from mice not in of plasma HDL cholesterol levels, suggesting that and to HDL cholesterol levels in M. K. expression of ABCA1 to plasma HDL Clin. Invest. 2001; 108: PubMed Scopus Google Scholar). in lipid and the of the liver to is to a major to plasma HDL observations that of ABCA1 in the liver may a at plasma HDL cholesterol levels and from to it is to determine may an of hepatic ABCA1 expression that results in a selective increase in plasma HDL lipid is by the liver, it is to not how the regulation of ABCA1 in the liver affects lipid efflux and of HDL but how hepatic ABCA1 may plasma it is essential to how HDL cholesterol levels may by ABCA1 in as the transgenic to bacterial artificial chromosome transgenic mice human ABCA1 V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the of a that endogenous regulatory the ABCA1 and that ABCA1 is expressed with normal and that of liver by in to an increase in ABCA1 and to increased expression of the human ABCA1 in an as the endogenous gene V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). This appropriate regulation of ABCA1 results in a increase in plasma HDL cholesterol levels lipoprotein V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). by transgenic mice the of we that increased ABCA1 activity is with as as the of that and C. G. N. Clee S.M. N. Hayden M.R. ABCA1 activity Clin. Invest. PubMed Scopus Google Scholar). the transgenic as an for the of increased ABCA1 expression to endogenous on plasma lipid levels. In to how hepatic ABCA1 expression in the absence of its appropriate regulatory affects plasma HDL cholesterol levels, we an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus This ABCA1 to in the liver that it is from its normal regulatory and results with results of ABCA1 overexpression in the transgenic mice. In mice treated with doses of in to determine how the hepatic of ABCA1 plasma HDL cholesterol levels. Our results suggest that the and regulation of ABCA1 in the liver and in the regulation of plasma HDL cholesterol levels in The human ABCA1 an adenovirus the to for ABCA1 expression and for in cells in a the gene G. K.J.D. L. Kastelein Hayden M.R. of lipoprotein by gene 2000; 11: PubMed Scopus Google for control of by of The a and in and the at using the as by the The of the by the of of not the gene and cells in with and in cells in at a of the removed and cells with of in with for at which the an cells for efflux mice from on a in to doses of 5 × 108 × 108 × 109 and 1.5 × 109 for Ad-ABCA1, and 1.5 × 109 for The of to the of in to control for to in A total of of the of mice. mice of as a from the 3 by by and liver, and and at transgenic and control mice on as V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). in with from the of and the of as K. K. M. C. Roomp K. M. N. Zhang K. A. T. M. N. C. S. Hayden M.R. T. S. and of of ATP-binding cassette in with high-density lipoprotein Res. PubMed Scopus Google and by of to and using a the binding of as a control K. K. M. C. Roomp K. M. N. Zhang K. A. T. M. N. C. S. Hayden M.R. T. S. and of of ATP-binding cassette in with high-density lipoprotein Res. PubMed Scopus Google Scholar). using to the by using In ABCA1 levels to levels to control for the and from from at in for in in to and to by the of from liver using and using as by the The levels of human and ABCA1 by from 3 of total as A. A. N. Zhang O. Hayden M.R. ABCA1 and and levels of Invest. PubMed Scopus Google Scholar). cells and with of for cells and in with for which of lipid-free for as S. Clee S.M. B. K. K. A. A. Marcil M. S. Roomp K. Collins J. Zhang K. A. S. Genest Jr., J. Kastelein Hayden M.R. in ABCA1 normal of ABCA1 by and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). cholesterol and with and S. Clee S.M. B. K. K. A. A. Marcil M. S. Roomp K. Collins J. Zhang K. A. S. Genest Jr., J. Kastelein Hayden M.R. in ABCA1 normal of ABCA1 by and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). from the and first with to S. A. J. V. Zhang Wang M. G. Hayden M.R. A ATP-binding cassette A1 phospholipid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the and from at in bile at using a and at a and and at bile and cholesterol as T. T. G. and cholesterol excretion of the liver is of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and by as T. T. G. and cholesterol excretion of the liver is of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a for at at plasma at and lipoprotein lipid cholesterol and by to using as C. G. N. Clee S.M. N. Hayden M.R. ABCA1 activity Clin. Invest. PubMed Scopus Google Scholar). HDL cholesterol levels of with levels of by an using a specific as C. G. N. Clee S.M. N. Hayden M.R. ABCA1 activity Clin. Invest. PubMed Scopus Google Scholar). the and of mice in Day 3 plasma in mice by from treated to expressed as the to the observed in mice. in plasma in transgenic mice by in transgenic mice on a V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google to observed in on the expressed as to the in the and from at mice. by with a using and activity of the first in cells express endogenous ABCA1 and a of cholesterol cells with at a of of ABCA1 expression as as cholesterol and efflux a dose-dependent increase in cholesterol efflux in cells the activity of Ad-ABCA1, mice doses of ranging from × 108 to 1.5 × 109 at 1.5 × 109 as a by and 3 and with an to expression levels in with ABCA1 expression observed in the liver M. of for hepatic gene PubMed Scopus Google which a dose-dependent of ABCA1 expression an 8.3-fold increase in ABCA1 levels observed in with the of × 109 at 3 which by by Day increase in ABCA1 expression observed in not of from of mice that the increase in ABCA1 levels from expression of human ABCA1 and not by of endogenous ABCA1 not results that ABCA1 increased in a dose-dependent in the of mice. HDL cholesterol levels increased in mice with and and maximal of HDL cholesterol observed at Day 3 in all Ad-ABCA1-treated mice Day HDL cholesterol levels to as to the in ABCA1 expression in the liver at that time the of × 108 which in a 1.2-fold increase in ABCA1 expression a increase in plasma HDL cholesterol levels doses of × 108 and × 109 did not in further of plasma HDL cholesterol, a increase in hepatic ABCA1 levels, HDL cholesterol levels increased by in mice treated with the of × 109 that in an 8.3-fold overexpression in hepatic ABCA1 levels results that increased hepatic ABCA1 HDL cholesterol, in with in ABCA1 transgenic mice V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google in Ad-ABCA1-treated × × × × × ATP binding cassette transporter apolipoprotein total to mice. in a new ATP binding cassette transporter apolipoprotein total to mice. results the first that the normal regulation of ABCA1 is to for and plasma HDL with the Ad-ABCA1-treated mice, the increase in plasma HDL cholesterol levels observed in transgenic in which a increase in expressed ABCA1 in the liver to increase plasma HDL cholesterol levels by V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the transgenic mice express the ABCA1 using endogenous regulatory sequences the we the that increased ABCA1 in may to the increase in plasma HDL cholesterol levels. ABCA1 may in the regulation of lipoprotein and increased ABCA1 expression in transgenic mice may to the increase in HDL cholesterol levels observed in it is that ABCA1 in the liver a major role in of HDL cholesterol levels in the transgenic mice not to but to the of ABCA1 expression with A. A. N. Zhang O. Hayden M.R. ABCA1 and and levels of Invest. PubMed Scopus Google Scholar). In to increased HDL cholesterol levels, we observed increased non-HDL cholesterol, and levels in mice with In mice the of × 109 the in plasma for non-HDL cholesterol levels, which nearly of control mice at Day 3 and at that of control mice at Day we observed a dose-dependent increase in that in a nearly increase in levels on 3 and in mice treated with 1.5 × 109 pfu of in the levels of and not of cholesterol that the in cholesterol to in the of results suggest that the 8.3-fold overexpression of ABCA1 in mice 1.5 × 109 pfu of in increased cholesterol in in plasma in mice, suggesting that the did not plasma of liver from mice at doses not we observed in bile and cholesterol levels in Ad-ABCA1-treated mice with not observations suggest that the altered lipid in mice that to from liver results suggest that the levels of ABCA1 with the of ABCA1 from its normal regulatory for the in plasma is not to the in plasma in mice treated with doses of × 109 to observed in the transgenic mice, ABCA1 expression is increased to 8.3-fold in Ad-ABCA1-treated mice with in transgenic mice mice treated with doses of to × 108 a to increase in ABCA1 expression comparable to the transgenic mice in of hepatic ABCA1 levels This the to determine the of appropriate regulation of ABCA1 in the liver with the of hepatic ABCA1 in a selective increase in plasma HDL cholesterol levels. the in plasma observed in transgenic mice with and to in Day 3 plasma observed in Ad-ABCA1-treated mice, which to plasma lipid in with Ad-ABCA1-treated mice. The in total cholesterol, triglycerides, HDL cholesterol, and non-HDL cholesterol levels transgenic mice, Ad-ABCA1-treated mice, and treated mice. in transgenic mice to and expressed as from the observed in the control in mice to observed mice with and expressed as from the in mice. in is the and the overexpression of ABCA1 is the the and from at mice This at comparable expression levels in the liver, levels in the transgenic mice to higher than in Ad-ABCA1-treated mice, which for by a selective increase in HDL cholesterol levels a transgenic mice that a increase of ABCA1 and mice treated with × 108 pfu of that a increase in The transgenic mice a increase in and a increase in HDL cholesterol levels with V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the Ad-ABCA1-treated mice a increase in and a increase in HDL cholesterol levels with results suggest higher hepatic ABCA1 levels in the Ad-ABCA1-treated mice with the transgenic mice, of ABCA1 than the in a selective increase in plasma HDL cholesterol levels in HDL cholesterol levels higher in the transgenic mice than in Ad-ABCA1-treated mice at further the that ABCA1 expressed under the control of endogenous regulatory is more to increase HDL cholesterol than ABCA1 expressed from an promoter. The Ad-ABCA1-treated mice not comparable to the transgenic mice, at comparable expression levels in the liver, transgenic ABCA1 is in in the transgenic we the that ABCA1 expression in hepatic as as may play a role in plasma HDL cholesterol levels in the transgenic mice. transgenic to the of hepatic with ABCA1 in HDL cholesterol in plasma in bacterial artificial chromosome transgenic with Ad-ABCA1-treated × × × × × bacterial artificial in a new bacterial artificial In to a on plasma HDL cholesterol levels, in in that not observed in the transgenic mice. transgenic mice in non-HDL cholesterol levels with In non-HDL cholesterol levels in mice that to 1.5 × 109 pfu of non-HDL cholesterol levels not 3 mice with the of × 108 a increase in non-HDL cholesterol in mice by Day with results suggest that at expression levels, regulation of ABCA1 to in plasma than HDL The of ABCA1 as a critical in the generation of HDL to the that an increase in ABCA1 elevate plasma HDL cholesterol levels and (1Hayden M.R. Clee S.M. Brooks-Wilson A. Genest Jr., J. Attie A. Kastelein J.J.P. Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency.Curr. Opin. Lipidol. 2000; 11: 117-122Crossref PubMed Scopus (109) Google Scholar, A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Crossref PubMed Scopus (1509) Google Scholar, S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Collins J.A. N. T. T. Boucher B. C. C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in for ABCA1 by cholesterol efflux levels and by Clin. Invest. 2000; PubMed Scopus Google Scholar). This in the transgenic human ABCA1 is expressed from its endogenous regulatory on a bacterial artificial In mice, ABCA1 overexpression in is increased endogenous which results in a increase in plasma HDL cholesterol V. Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 transgenic mice increased and efflux by an in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the of ABCA1 to the of C. G. N. Clee S.M. N. Hayden M.R. ABCA1 activity Clin. Invest. PubMed Scopus Google Scholar). In contrast, an ABCA1 transgenic showed results with to from In the ABCA1 transgenic mice, ABCA1 expression is by the that ABCA1 overexpression to the liver and G. M. C. T. J. Brewer Jr., S. ABCA1 overexpression to and increased cholesterol excretion in transgenic Clin. Invest. 2001; 108: PubMed Scopus Google Scholar). of mice with of the human ABCA1 which results in a of plasma HDL cholesterol on a G. M. C. T. J. Brewer Jr., S. ABCA1 overexpression to and increased cholesterol excretion in transgenic Clin. Invest. 2001; 108: PubMed Scopus Google Scholar). mice a increased ABCA1 to the lipid and C.W. G. B. J. Jr., Brewer Jr., The ATP binding cassette transporter A1 (ABCA1) the of in and PubMed Scopus Google Scholar). increased observed mice an C.W. G. B. J. Jr., Brewer Jr., The ATP binding cassette transporter A1 (ABCA1) the of in and PubMed Scopus Google Scholar). results the of ABCA1 and expression in to plasma HDL cholesterol levels and from in To how hepatic ABCA1 expression to plasma we an to human ABCA1 in the liver and the dose-dependent of ABCA1 expression on plasma lipid and lipoprotein The in first in by cholesterol and efflux in and In of ABCA1 in an increase in plasma HDL cholesterol levels as that hepatic ABCA1 in HDL cholesterol homeostasis. at comparable expression levels, HDL cholesterol increased by in Ad-ABCA1-treated mice with a increase in transgenic suggesting that transgenic expression of ABCA1 from the is more in plasma HDL cholesterol levels than ABCA1 with an In we observed a of ABCA1 on the lipid which at doses of that in a 8.3-fold overexpression of hepatic the levels of non-HDL cholesterol, and all increased in Ad-ABCA1-treated mice in a dose-dependent manner, and the of that of the increase in HDL cholesterol levels. a dose-dependent increase in and non-HDL cholesterol levels observed in transgenic mice, did not and it is not to to regulation of ABCA1 ABCA1 expression by the G. M. C. T. J. Brewer Jr., S. ABCA1 overexpression to and increased cholesterol excretion in transgenic Clin. Invest. 2001; 108: PubMed Scopus Google Scholar). observations suggest that hepatic ABCA1 plasma of is that the of hepatic ABCA1 expression affects lipid homeostasis. observed on cholesterol levels in the transgenic mice in mice treated with the of Ad-ABCA1, which in levels of ABCA1 overexpression in the liver and the in a and dose-dependent increase in non-HDL cholesterol levels. This a increase in hepatic ABCA1 may increase HDL cholesterol, excessive ABCA1 may lipid by the transfer of excess cholesterol to of This may observed ABCA1 is in the absence of appropriate regulatory A is that appropriate regulation of ABCA1 may critical for HDL In lipid is control of hepatic the in the human ABCA1 it is that that the appropriate of ABCA1 to the J.A. C. N. S. Brewer Jr., The ABCA1 transporter functions on the of Res. PubMed Scopus (69) Google Scholar, A. Hayden M.R. Attie ABCA1 is essential for cholesterol efflux the of cholesterol in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to of ABCA1 S. A. J. V. Zhang Wang M. G. Hayden M.R. A ATP-binding cassette A1 phospholipid Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of ABCA1 may play in appropriate of is that ABCA1 expression in may to a selective increase in plasma HDL cholesterol levels. In the transgenic mice, the of endogenous regulatory that transgenic ABCA1 is in all it is in a overexpression of ABCA1 the is that the of hepatic and ABCA1 to the increase in HDL cholesterol levels in the transgenic mice with Ad-ABCA1-treated mice at comparable expression levels. ABCA1 to to plasma HDL cholesterol levels in M. K. expression of ABCA1 to plasma HDL Clin. Invest. 2001; 108: PubMed Scopus Google it is that as the may HDL cholesterol in ABCA1 in on of ABCA1 to mice L. A. J. T. J. N. S. Brewer Jr., of the hepatic ABCA1 transporter in cholesterol and plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google the the a ABCA1 to we an human ABCA1 The by × 108 which in an increase in ABCA1 by to L. A. J. T. J. N. S. Brewer Jr., of the hepatic ABCA1 transporter in cholesterol and plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google is comparable to the in × 108 which in a 1.2-fold increase in ABCA1 by 3 of results of of ABCA1 in of × 108 × × 109 of to and to by to to by to to by to by in a new observed maximal in plasma with the major a to increase in HDL cholesterol, and levels, and a increase in L. A. J. T. J. N. S. Brewer Jr., of the hepatic ABCA1 transporter in cholesterol and plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In on non-HDL cholesterol levels, in to observations in the transgenic mice G. M. C. T. J. Brewer Jr., S. ABCA1 overexpression to and increased cholesterol excretion in transgenic Clin. Invest. 2001; 108: PubMed Scopus Google Scholar, L. A. J. T. J. N. S. Brewer Jr., of the hepatic ABCA1 transporter in cholesterol and plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). observed in and expression levels that in as as L. A. J. T. J. N. S. Brewer Jr., of the hepatic ABCA1 transporter in cholesterol and plasma Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). maximal in plasma at Day 3 suggesting that the in plasma lipid levels to in the of the in plasma in the transgenic mice and Ad-ABCA1-treated mice at comparable expression levels showed that HDL cholesterol levels increased more in the transgenic This that regulation of in the liver and in may critical for HDL cholesterol levels. ABCA1 may function with to to HDL. In the Ad-ABCA1-treated mice, increased ABCA1 expression is from hepatic as as that may to HDL cholesterol levels. ABCA1 is under regulation at and levels, and appropriate levels in cells of and with to critical for the of ABCA1 to increase HDL cholesterol levels. ABCA1 activity in may HDL cholesterol in Our results suggest that on ABCA1 expression the endogenous that appropriate regulation of The to and for the of This is by the of and the and of the of of and is a and is a of a

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