The Lipidation by Hepatocytes of Human Apolipoprotein A-I Occurs by Both ABCA1-dependent and -independent Pathways

The pathways of hepatic intra- and peri-cellular lipidation of apolipoprotein A-I (apoA-I) were studied by infecting primary mouse hepatocytes from either apoA-I-deficient or ABCA1-deficient mice with a recombinant adenovirus expressing the human apoA-I (hapoA-I) cDNA (endo apoA-I) or incubating the hepatocytes with exogenously added hapoA-I (exo apoA-I) and examining the hapoA-I-containing lipoproteins formed. The cells, maintained in serum-free medium, were labeled with [3H]choline, and the cell medium was separated by fast protein liquid chromatography or immunoprecipitated to quantify labeled choline phospholipids specifically associated with hapoA-I. With the apoA-I-deficient hepatocytes, the high density lipoprotein fraction formed with endo apoA-I contained proportionally more phospholipids than that formed with exo apoA-I. However, the lipoprotein size and electrophoretic mobility and phospholipid profiles were similar for exo apoA-I and endo apoA-I. Taken together, these data demonstrate that a significant proportion of hapoA-I is secreted from hepatocytes in a phospholipidated state but that hapoA-I is also phospholipidated peri-cellularly. With primary hepatocytes from ABCA1-deficient mice, the expression and net secretion of adenoviral-generated endogenous apoA-I was unchanged compared with control mice, but3H-phospholipids associated with endo apoA-I and exo apoA-I decreased by 63 and 25%, respectively. The lipoprotein size and electrophoretic migration and their phospholipid profiles remained unchanged. In conclusion, we demonstrated that intracellular and peri-cellular lipidation of apoA-I represent distinct and additive pathways that may be regulated independently. Hepatocyte expression of ABCA1 is central to the lipidation of newly synthesized apoA-I but also contributes to the lipidation of exogenous apoA-I. However, a significant basal level of phospholipidation occurs in the absence of ABCA1. The pathways of hepatic intra- and peri-cellular lipidation of apolipoprotein A-I (apoA-I) were studied by infecting primary mouse hepatocytes from either apoA-I-deficient or ABCA1-deficient mice with a recombinant adenovirus expressing the human apoA-I (hapoA-I) cDNA (endo apoA-I) or incubating the hepatocytes with exogenously added hapoA-I (exo apoA-I) and examining the hapoA-I-containing lipoproteins formed. The cells, maintained in serum-free medium, were labeled with [3H]choline, and the cell medium was separated by fast protein liquid chromatography or immunoprecipitated to quantify labeled choline phospholipids specifically associated with hapoA-I. With the apoA-I-deficient hepatocytes, the high density lipoprotein fraction formed with endo apoA-I contained proportionally more phospholipids than that formed with exo apoA-I. However, the lipoprotein size and electrophoretic mobility and phospholipid profiles were similar for exo apoA-I and endo apoA-I. Taken together, these data demonstrate that a significant proportion of hapoA-I is secreted from hepatocytes in a phospholipidated state but that hapoA-I is also phospholipidated peri-cellularly. With primary hepatocytes from ABCA1-deficient mice, the expression and net secretion of adenoviral-generated endogenous apoA-I was unchanged compared with control mice, but3H-phospholipids associated with endo apoA-I and exo apoA-I decreased by 63 and 25%, respectively. The lipoprotein size and electrophoretic migration and their phospholipid profiles remained unchanged. In conclusion, we demonstrated that intracellular and peri-cellular lipidation of apoA-I represent distinct and additive pathways that may be regulated independently. Hepatocyte expression of ABCA1 is central to the lipidation of newly synthesized apoA-I but also contributes to the lipidation of exogenous apoA-I. However, a significant basal level of phospholipidation occurs in the absence of ABCA1. high density lipoprotein ATP binding cassette transporter A1 adenovirus serotype 5 Ad5 adenoviral construct expressing human apolipoprotein A-I Ad5 adenoviral construct expressing firefly luciferase apolipoprotein endogenously synthesized exogenously added fast protein liquid chromatography human apolipoprotein A-I low density lipoprotein polyacrylamide gradient gel electrophoresis phosphatidylcholine phosphatidylethanolamine phosphatidylinositol phosphatidylserine retinoid X receptor peroxisome proliferator-activated receptor sphingomyelin thin layer chromatography very high density lipoprotein very low density lipoprotein. The hepatic and intestinal origins of the major high density lipoprotein (HDL)1apolipoproteins, apolipoprotein (apo)A-I and apoA-II, are well defined (1Eisenberg S. J. Lipid Res. 1984; 25: 1017-1058Abstract Full Text PDF PubMed Google Scholar, 2Zannis V.I. Kardassis D. 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The were with and by with The size of the apoA-I were compared with of and the of secreted apoA-I was compared with apoA-I and HDL from human secreted from hepatocytes was immunoprecipitated either from the medium or from lipoprotein by as The were with a apoA-I from and protein of from not with was as a control The were and with of and in a of of were either to or were by and lipid J. PubMed Scopus Google Scholar) and thin layer chromatography was gel and a for of phosphatidylcholine and The to phosphatidylcholine and sphingomyelin were and for were labeled with to cellular were as with with [3H]choline, in medium was added adenoviral the also the as for the the hepatocytes were as and in in the absence or of apoA-I for The hapoA-I-containing lipoproteins were immunoprecipitated as and phospholipids were by the of and J. PubMed Scopus Google Scholar). The phospholipids were separated by in the of a of The was to a and the relative of phospholipids were by are as the of to control for and of a newly synthesized apoA-I from the to the cell and through lipid the relative contribution to the lipidation we compared endogenously synthesized apoA-I and exogenously added apoA-I. hepatocytes were from mice by and were in the of serum-free The were with either adenoviral construct human apoA-I or luciferase for and to The the were and with in the absence or of exogenous hapoA-I for was to secretion of hapoA-I for and peri-cellular a of exo apoA-I that the of hapoA-I secreted the The hapoA-I-containing lipoproteins in the were by a of The adenoviral was specifically to apoA-I and secretion of The electrophoretic migration of hapoA-I newly secreted from primary hepatocytes to as endogenously synthesized apoA-I or or exogenously added hapoA-I to as was apoA-I and exo apoA-I from apoA-I-deficient mice were to have and apoA-I with is in with a in hepatocytes C.K. Pape M.E. Marotti K.R. Melchior G.W. J. Lipid Res. 1991; 32: 439-447Abstract Full Text PDF PubMed Google Scholar), lipoproteins were to and lipoproteins formed by hepatocytes from mice endo apoA-I or exo apoA-I that HDL the have similar electrophoretic and a significant the lipoprotein size of apoA-I secreted by the hepatocytes expressing the medium was and by and The of human apoA-I and and in the were by hapoA-I well separated The lipoproteins a for fraction also with the of lipoproteins data not The of lipoproteins the of and the to and apoA-I The are of The of apoA-I of medium lipoproteins that endo apoA-I and exo apoA-I lipoproteins of similar from to and and the with control hepatocytes in and exo apoA-I was added to the medium of hepatocytes with the of associated with apoA-I was additive not that lipidation occurs and control and mouse hepatocytes were also with or and by for size of the endo and exo the profiles of hapoA-I-containing lipoproteins from control and ABCA1-deficient hepatocytes, a be in the proportion of hapoA-I in the and HDL for endo apoA-I and exo apoA-I demonstrate the contribution of ABCA1 to intracellular and peri-cellular lipidation of apoA-I. The different lipoprotein by the primary hepatocytes and separated by and were by and of hapoA-I were from lipoprotein The lipoprotein for different was and The endo apoA-I in and are well separated from The and apoA-I distinct are with the of lipoproteins with of apoA-I and with of of hapoA-I is secreted as with a significant size in this The lipoprotein from the of hepatocytes with exo apoA-I were also by HDL and in to endo lipidation of exo apoA-I profiles of as well as hapoA-I-containing lipoproteins and 5 and and in endo apoA-I and exo apoA-I lipoproteins are and also that lipidation associated with secretion and hepatocytes with and with exo apoA-I were with a retinoid X receptor the hapoA-I-containing HDL and were similar to control exo apoA-I of HDL is that lipidation of exogenous hapoA-I. The was not with endo apoA-I not and were the hapoA-I-containing lipoprotein by control and hepatocytes HDL and from control hepatocytes with exo apoA-I are to HDL and from exo apoA-I in for endo the HDL and for the control hepatocytes were very similar to the HDL and from that the of hapoA-I in and HDL is in hepatocytes and the of the lipoprotein formed is unchanged. the apoA-I-deficient hepatocytes, the relative of endo apoA-I in the different lipoprotein is shown in A. of the endo apoA-I secreted was in a but significant of secreted apoA-I was also associated with the is in with in hepatocytes C.K. Pape M.E. Marotti K.R. Melchior G.W. J. Lipid Res. 1991; 32: 439-447Abstract Full Text PDF PubMed Google Scholar) and in cells, the not and have lipoproteins in this lipoprotein size J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar, T.M. J. L. Shore V.G. PubMed Scopus Google Scholar). The of phospholipids with hapoA-I in the was by of hapoA-I of the lipoprotein as and in were immunoprecipitated with in also in not with was and as The that the of secreted hapoA-I is in the fraction a significant of the phospholipid associated with apoA-I is in the lipoprotein this that apoA-I be secreted with significant of is with the size and of hapoA-I in the as by formed by lipidation of exo apoA-I were in the to and were and immunoprecipitated with hapoA-I and the associated with apoA-I as proportion of apoA-I was in the HDL fraction for exo apoA-I compared with endo apoA-I. significant of the phospholipids were associated with the this that apoA-I significant of phospholipid is with the size and of hapoA-I in the as by of hapoA-I and phospholipids in the different lipoprotein of control and hepatocytes were also was a significant in endo apoA-I associated with the HDL in hepatocytes compared with control hepatocytes in was also to a was also a significant data not in from the hepatocytes compared with control was a of apoA-I and in the fraction of hepatocytes compared with control hepatocytes, not exo was a in of exo apoA-I with the HDL fraction for hepatocytes compared with control hepatocytes with a in were also decreased data not the of hapoA-I secreted by control and hepatocytes was the that ABCA1 not secretion of apoA-I control ABCA1 phospholipids were separated by and endo apoA-I and exo of the was in phosphatidylcholine with the in sphingomyelin not a more of phospholipid hepatocytes were with to as phospholipids sphingomyelin phosphatidylcholine phosphatidylinositol phosphatidylserine and phosphatidylethanolamine were separated by and by of the and the were significant the of the phospholipid associated with endo apoA-I and exo apoA-I for apoA-I ABCA1 and ABCA1 hepatocytes not is a that the in the of hapoA-I or phospholipids in the the and of the lipoproteins are unchanged in the absence of ABCA1. with or were labeled with and the medium a were were with and to ABCA1 and the of ABCA1 in the lipidation of endo apoA-I or exo apoA-I. The shown is the of in In hepatocytes, not the of associated with but in a but in the lipidation of newly secreted apoA-I. In a lipidation of endo apoA-I. were for the with or of exogenously added hapoA-I and were of exo apoA-I were added to the of of hapoA-I protein of in a significant in lipidation of in a more but significant in lipidation of exo apoA-I the labeled phospholipid associated with but not the of the of and not shown are the of 5 of exo and are of with of exo apoA-I. The of the were to the contribution of secretion and efflux pathways to the lipidation of apoA-I by hepatocytes and the of ABCA1 in these ABCA1 not the net secretion of apoA-I by the adenoviral the of endogenously or exogenously the of the relative of apoA-I and phospholipids in the different lipoprotein ABCA1 the proportion of apoA-I in the HDL the proportion of lipid associated with the HDL and the from hepatocytes, but not the of apoA-I compared with control that HDL formed by endogenously synthesized apoA-I was more by ABCA1 than that formed by exogenously added apoA-I. ABCA1 contributes to lipidation of apoA-I not by the well efflux (9Oram J.F. Lawn R.M. Garvin M.R. Wade D.P. J. Biol. Chem. 2000; 275: 34508-34511Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, 10Wang N. Silver D.L. Costet P. Tall A.R. J. Biol. Chem. 2000; 275: 33053-33058Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 11Wang N. Silver D.L. Thiele C. Tall A.R. J. Biol. 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In we also of apoA-I expression in the ABCA1-deficient hepatocytes compared with control ABCA1 the of HDL formed by the lipidation of apoA-I. However, is a significant basal level of lipidation of apoA-I in the absence of ABCA1, for endo apoA-I and exo apoA-I. is of hepatic apoA-I is this of of lipidation by the be to of Tangier HDL lipidation in or the to the The of the lipidation is that be a in may also be Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). have a the of H. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and hepatocytes M. D. S. and L. in as we have not to this binding also but the of lipidation of newly secreted with for and J.F. T. Biol. 2001; PubMed Scopus Google Scholar, T. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar, M. M. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. T. A. S. P. G. J. 2001; PubMed Scopus Google Scholar). In the of lipidation pathway. The absence of HDL by gel the absence of a significant M. D. S. V. M. and L. that cholesterol with lipoproteins and is to be secreted by the hepatocytes PubMed Scopus Google Scholar, L. J. PubMed Scopus Google Scholar). The is as to HDL is not formed. of apoA-I with hepatocytes data not were not to a for HDL may not be hepatocytes but cell and and are the to apoA-I Forte T.M. Shore V.G. J. Lipid Res. Full Text PDF PubMed Google Scholar) studied lipoprotein secretion from serum-free to the in this of cell medium by a with the of apoA-I in the or However, not and not apoA-I was in this lipoprotein Forte T.M. Shore V.G. J. Lipid Res. Full Text PDF PubMed Google Scholar). In of apoA-I and of associated with the ABCA1 but not endo apoA-I and phospholipid associated with but not exo apoA-I. to the of apoA-I with secreted from hepatocytes from control and ABCA1-deficient also the of ABCA1 in the secretion of and associated in of the in in with Tangier hepatocytes in also secreted nascent apoA-I C.K. Pape M.E. Marotti K.R. Melchior G.W. J. Lipid Res. 1991; 32: 439-447Abstract Full Text PDF PubMed Google Scholar). the very in secreted apoA-I was in The from that to to the of that secreted apoA-I was in the medium and to the of in the for of of apoA-I. to the of protein in hepatocytes and also that the lipidation of newly secreted as ABCA1. is to from S. G. Forte T.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar), J. Lipid Res. Full Text PDF PubMed Google Scholar), and mouse A. Cladaras C. Zanni E.E. V.I. 1991; PubMed Scopus Google Scholar), have with apoA-I and to of these apoA-I by than that not by J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar) the lipidation state of newly secreted apoA-I from The that of newly secreted apoA-I is and is In the cell primary was to nascent HDL and was to the secreted lipoproteins by as and With this a significant of of hapoA-I is secreted as HDL with in with the of J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). The of a major for ABCA1 in phospholipid and cholesterol efflux to nascent HDL or apoA-I a in the by apoA-I is have studied ABCA1 in and and shown that this transporter is for efflux of cholesterol and phospholipid to apoA-I. J.A. C. N. S. Brewer Res. PubMed Scopus Google Scholar) demonstrated that protein was to the of cells, a cell and cholesterol of ABCA1 in mice to HDL expression was not specifically to the G. M. C. T. J. Brewer S. J. 2001; PubMed Scopus Google Scholar). major of ABCA1 in apoA-I lipidation with the of ABCA1 in the R.M. Wade D.P. Biol. 2001; PubMed Scopus Google Scholar, V. Clee S.M. Zhang L.H. A. A. N. C. M.R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, V. J.F. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). L. C. A. J. T. M. J. N. S. Brewer J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that of a adenoviral ABCA1 construct mice in cholesterol efflux and is the to the of ABCA1 in the of apoA-I In conclusion, we demonstrated that intracellular and peri-cellular lipidation of apoA-I represent distinct and additive pathways that may be regulated independently. Hepatocyte expression of ABCA1 is central to the lipidation of newly synthesized but pathway may also to the lipidation of apoA-I. the lipidation of apoA-I by cholesterol and the of lipidation of apoA-I by hepatic cholesterol for of the

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