Hepatic CTP:Phosphocholine Cytidylyltransferase-α Is a Critical Predictor of Plasma High Density Lipoprotein and Very Low Density Lipoprotein

CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine (PC). We previously generated a mouse in which the hepatic CTα gene was specifically inactivated by the cre/loxP procedure. In CTα knock-out mice, plasma high density lipoprotein (HDL) and very low density lipoprotein (VLDL) levels were markedly lower than in wild type mice (Jacobs, R. L., Devlin, C., Tabas, I., and Vance, D. E. (2004) J. Biol. Chem. 279, 47402-47410.) To investigate the mechanism(s) responsible for the decrease in plasma lipoprotein levels, we isolated primary hepatocytes from knock-out and wild type mice. ABCA1 expression was reduced in knock-out hepatocytes and apoAI-dependent cholesterol, and PC efflux was impaired. When knock-out hepatocytes were infected with an adenovirus expressing CTα, apoAI-dependent PC efflux returned partially, whereas cholesterol efflux and ABCA1 levels were not restored to normal levels. Adenoviral expression of CTα did not increase VLDL secretion in knock-out hepatocytes, even though cellular PC levels returned to normal. However, in vivo adenoviral delivery of CTα normalized plasma HDL and VLDL levels in knock-out mice. The observations demonstrate that hepatic PC biosynthesis is a key player in maintaining plasma VLDL and HDL, and further underscores the importance of the liver in HDL formation. CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine (PC). We previously generated a mouse in which the hepatic CTα gene was specifically inactivated by the cre/loxP procedure. In CTα knock-out mice, plasma high density lipoprotein (HDL) and very low density lipoprotein (VLDL) levels were markedly lower than in wild type mice (Jacobs, R. L., Devlin, C., Tabas, I., and Vance, D. E. (2004) J. Biol. Chem. 279, 47402-47410.) To investigate the mechanism(s) responsible for the decrease in plasma lipoprotein levels, we isolated primary hepatocytes from knock-out and wild type mice. ABCA1 expression was reduced in knock-out hepatocytes and apoAI-dependent cholesterol, and PC efflux was impaired. When knock-out hepatocytes were infected with an adenovirus expressing CTα, apoAI-dependent PC efflux returned partially, whereas cholesterol efflux and ABCA1 levels were not restored to normal levels. Adenoviral expression of CTα did not increase VLDL secretion in knock-out hepatocytes, even though cellular PC levels returned to normal. However, in vivo adenoviral delivery of CTα normalized plasma HDL and VLDL levels in knock-out mice. The observations demonstrate that hepatic PC biosynthesis is a key player in maintaining plasma VLDL and HDL, and further underscores the importance of the liver in HDL formation. In mammals, phosphatidylcholine (PC) 4The abbreviations used are: PCphosphatidylcholineABCA1ATP-binding cassette transporter A1apoapolipoproteinAd.adenovirusCTCTP: phosphocholine cytidylyltransferaseDMEMDulbecco's modified Eagle's mediumFBSfetal bovine serumGFPgreen fluorescent proteinHAhemagglutininHDLhigh density lipoproteinPEphosphatidylethanolaminePEMTphosphatidylethanolamine N-methyltransferasePDIprotein-disulfide isomeraseTGtriacylglycerolVLDLvery low density lipoprotein. is the primary phospholipid in cellular membranes, bile, lung surfactant, and plasma lipoproteins. In all nucleated tissues, PC is made via the Kennedy (CDP-choline) pathway (1Kennedy E.P. Weiss S.B. J. Biol. Chem. 1956; 222: 193-214Abstract Full Text PDF PubMed Google Scholar), and the activity of CTP: phosphocholine cytidylyltransferase (CT) usually regulates the flux through this pathway (2Vance D.E. Biochem. Cell Biol. 1990; 68: 1151-1165Crossref PubMed Scopus (147) Google Scholar, 3Johnson J.E. Kalmar G.B. Sohal P.S. Walkey C.J. Yamashita S. Cornell R.B. Biochem. J. 1992; 285: 815-820Crossref PubMed Scopus (45) Google Scholar, 4Lykidis A. Jackson P. Jackowski S. Biochemistry. 2001; 40: 494-503Crossref PubMed Scopus (43) Google Scholar). In mice, as in humans, two genes named Pcyt1a and Pcyt1b, encode CT (5Karim M. Jackson P. Jackowski S. Biochim. Biophys. Acta. 2003; 1633: 1-12Crossref PubMed Scopus (78) Google Scholar). The gene product of Pcyt1a, CTα, is believed to be the predominant isoform in liver (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 7Jacobs R.L. Stead L.M. Devlin C. Tabas I. Brosnan M.E. Brosnan J.T. Vance D.E. J. Biol. Chem. 2005; 280: 28299-28305Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). PC is also synthesized in the liver via the sequential methylation of phosphatidylethanolamine (PE) catalyzed by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT) (8Vance D.E. Ridgway N.D. Prog. Lipid Res. 1988; 27: 61-79Crossref PubMed Scopus (201) Google Scholar). Several studies have indicated that ∼30% of the PC in liver is made via the PEMT pathway, whereas the remainder is synthesized via the CDP-choline pathway (9Sundler R. Akesson B. Biochem. J. 1975; 146: 309-315Crossref PubMed Scopus (70) Google Scholar, 10Reo N.V. Adinehzadeh M. Foy B.D. Biochim. Biophys. Acta. 2002; 1580: 171-188Crossref PubMed Scopus (91) Google Scholar, 11DeLong C.J. Shen Y.J. Thomas M.J. Cui Z. J. Biol. Chem. 1999; 274: 29683-29688Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar). phosphatidylcholine ATP-binding cassette transporter A1 apolipoprotein adenovirus CTP: phosphocholine cytidylyltransferase Dulbecco's modified Eagle's medium fetal bovine serum green fluorescent protein hemagglutinin high density lipoprotein phosphatidylethanolamine phosphatidylethanolamine N-methyltransferase protein-disulfide isomerase triacylglycerol very low density lipoprotein. The function of both PC biosynthetic pathways has been a topic of interest in our laboratory for many years. Recently, we generated mice deficient in either PEMT or hepatic CTα, allowing us to gain insight into the role of these pathways in lipid metabolism. Pemt-/- mice appear normal when fed a chow diet, suggesting that the CDP-choline pathway is sufficient for life, providing that dietary choline is available (12Walkey C.J. Donohue L.R. Bronson R. Agellon L.B. Vance D.E. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12880-12885Crossref PubMed Scopus (139) Google Scholar, 13Walkey C.J. Yu L. Agellon L.B. Vance D.E. J. Biol. Chem. 1998; 273: 27043-27046Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 14Waite K.A. Cabilio N.R. Vance D.E. J. Nutr. 2002; 132: 68-71Crossref PubMed Scopus (64) Google Scholar). However, a specific role for PEMT in VLDL secretion has been demonstrated in vivo and in hepatocyte experiments (15Noga A.A. Zhao Y. Vance D.E. J. Biol. Chem. 2002; 277: 42358-42365Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 16Noga A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). In male Pemt-/- mice fed a high fat/cholesterol diet, plasma triacylglycerol (TG) and PC levels were decreased with A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). In Pemt-/- hepatocytes, and secretion was reduced by and A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). in VLDL secretion in the Pemt-/- mice even though hepatic CT activity was A.A. Vance D.E. J. Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). hepatic PC was the in Pemt-/- mice and wild type A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). studies demonstrate that CT not for the of PEMT that PC is in maintaining VLDL secretion from The function of CTα has been in modified mouse of CTα expression is L. S. Tabas I. Jackowski S. Biol. 2005; PubMed Scopus Google Scholar). of CTα has been in D. C. B. Jackowski S. Tabas I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), liver (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 7Jacobs R.L. Stead L.M. Devlin C. Tabas I. Brosnan M.E. Brosnan J.T. Vance D.E. J. Biol. Chem. 2005; 280: 28299-28305Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar), and lung Y. R. J.E. Jackowski S. Biol. 27: PubMed Scopus Google Scholar). Jackowski and Y. R. J.E. Jackowski S. Biol. 27: PubMed Scopus Google have that CTα is not for or of lung However, CTα is for the and secretion of PC in lung normal PC to and have CTα is not in the of is to D. C. B. Jackowski S. Tabas I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We previously that mice hepatic CTα and However, as a of CT the of PC in the liver is reduced by whereas (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). the levels of plasma lipoprotein cholesterol, and PC markedly The of plasma is to decreased secretion of VLDL from the liver (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). In to VLDL the hepatic PC and high density lipoprotein (HDL) has not been choline not plasma HDL levels in Vance D.E. Biochem. Cell Biol. 1990; 68: PubMed Scopus Google Scholar). the of cholesterol, or in the medium from hepatocytes with and medium is not reduced Vance D.E. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). was that both the Pemt-/- mice and the CTα knock-out mice lower HDL than wild type (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 16Noga A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). of the ATP-binding cassette transporter which both cellular and cholesterol to plasma by E. L.R. A. J. 2005; PubMed Scopus Google Scholar). We the that of PC biosynthesis the of PC available for of and in decreased levels of plasma hepatocytes as a we or not PC biosynthesis HDL formation. We that both VLDL secretion and HDL be in We also that CT activity were via adenoviral gene PC be available to both VLDL and HDL formation. was from and was from hemagglutinin and were from and and were from and to were from and were from was from were by the of and were in with of the mice were fed a chow or a and were to a and hepatocytes were isolated by and a density of in Dulbecco's modified Eagle's medium fetal bovine serum the were in a experiments VLDL hepatocytes were in for was Lipid from were with and with and for The were with and with with or for from and medium were J. M. J. Biol. Chem. Full Text PDF PubMed Google and by and the with PC and cholesterol was with a R.L. S. Vance D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Lipid efflux was as a of in the by the of the in and Adenoviral of a an CTα was into a with and into adenovirus for in S. Yu J. B. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). The also a gene green fluorescent protein the adenovirus used to CTα protein also which as a of and protein was used to the of adenovirus In hepatocytes were infected with or for the of the were in a density of the were with were for and in for with for were with the primary for The were with the primary for were for with both and were with and was a Cell and were in with and serum in a The were by the with either or which for The for CTα an was used in these were in medium and in medium of were the of the The were in serum for The medium was with that of in the of serum for The were and by and was of of or was into wild type or knock-out mice via the the mice were and with was and plasma were and for further of or medium was in and were were to an and with or were by to the of Lipid of cholesterol, and was in of medium and plasma of the with was as an and were The of cholesterol, and was by A. S. PubMed Scopus Google Scholar). were by and the of PC and was via a lipid J. Lipid Res. 1992; Full Text PDF PubMed Google Scholar). of lipid hepatocytes were a density of of in were with for with were with for with and a of and Lipid or medium was into lipoprotein high with an to a or for cholesterol cholesterol and PC were as previously (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). as to of was to of was to be VLDL in isolated from wild type and hepatic CTα mice were in for in hepatocytes PC and into the medium with wild type secretion was reduced by in knock-out hepatocytes, whereas secretion was VLDL secretion from with a increase in hepatocyte which in lipid these lipid were with lipid in which in the The decrease in VLDL secretion and of in knock-out have been a of phospholipid cellular PC levels were reduced by Lipid in previously that plasma HDL and levels were reduced in the CTα knock-out mouse (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). To the role of hepatic CTα in HDL we wild type and knock-out hepatocytes in the or of in and the efflux of and from wild type and knock-out hepatocytes was for The of and from wild type hepatocytes was by and by In knock-out a increase of secretion into the medium did not increase the of knock-out hepatocytes to with The of cholesterol in the medium was also of and that knock-out hepatocytes cholesterol efflux secretion was not by and the lipid efflux experiments that was protein of the by with the in HDL in the knock-out mice was that the of HDL was in the medium from knock-out hepatocytes with is with the in which that efflux was in knock-out hepatocytes by efflux of The protein ABCA1 a role in HDL by the efflux of cellular to an apolipoprotein M. M. M. R. 2005; PubMed Scopus Google Scholar). this in hepatocytes were and the levels of ABCA1 protein In with the efflux ABCA1 protein levels were reduced by in Adenoviral of CTα PC in the of lipid secretion was in knock-out hepatocytes, we a adenovirus that an CTα expression the CTα was into and the enzyme was to have in activity and to into PC not the protein was the When hepatocytes were infected with the the for CTα were by Adenoviral expression of CTα in wild type hepatocytes in a increase in of in PC from either or previously (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar), PC biosynthesis was reduced by in hepatocytes, whereas PC was reduced by Adenoviral CTα of knock-out in a and increase in and into adenoviral the of hepatic PC biosynthesis was in knock-out and wild type The of PC was lower in knock-out hepatocytes with restored PC to levels the of PC in wild type was not adenoviral suggesting of PC in these an the of PC was in infected with with However, the of PC in knock-out was not by CT Adenoviral of CTα Lipid to in investigate or not lipid efflux was by adenoviral expression of CTα, we hepatocytes with or or of CTα in wild type hepatocytes did not the of PC or cholesterol to and However, when knock-out were with the of PC in the medium by with that in hepatocytes, PC efflux lower than that in wild type experiments the efflux of and were and of knock-out hepatocytes normalized PC efflux to The of the HDL in the medium of knock-out was also returned to normal cholesterol efflux to was not which that the of cellular PC was not sufficient to HDL in To HDL was not normalized by adenoviral expression of CTα, we the levels of cellular PC levels returned to normal adenoviral of CTα, ABCA1 protein levels did not increase in knock-out hepatocytes with ABCA1 was also not in wild type expressing adenoviral Adenoviral of CTα VLDL from studies have a reduced hepatic PC biosynthesis and secretion (15Noga A.A. Zhao Y. Vance D.E. J. Biol. Chem. 2002; 277: 42358-42365Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 16Noga A.A. Vance D.E. J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, Vance D.E. Biochem. Cell Biol. 1990; 68: PubMed Scopus Google Scholar, Vance D.E. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). we that adenoviral expression of CTα, which normalized cellular PC increase VLDL secretion in knock-out However, the of from was not by and of CTα in wild type which did not cellular PC levels, in a in secretion of with did not cellular or cholesterol levels in either or hepatocytes not that of CTα in normal a in VLDL we that of CTα in the we with a CTα of the with low medium and high CTα not were to VLDL The CT were used as a When with for synthesized was not not The PC was of the of CTα than with not secretion was also reduced in CTα not is with our in primary hepatocytes and an role of high levels of CT VLDL In of CTα PC and in in vivo of hepatic CT activity plasma lipoprotein levels in the knock-out mice, we mice with either or via the liver and plasma were isolated and previously (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar), hepatic CT activity in knock-out mice was reduced to of levels CT activity was restored to wild type levels. The of CT in is whereas the of CT is to be an In activity in both and was normalized in knock-out mice levels of hepatic PC were reduced in knock-out mice with restored PC in knock-out to normal. to our hepatocyte the of was not by or adenoviral cholesterol was decreased in all lipoprotein in knock-out mice of CT activity in mice normalized cholesterol in HDL and VLDL not in low density lipoproteins. CT activity with plasma cholesterol In to hepatocytes, in vivo to knock-out mice ABCA1 levels was reduced by in knock-out mice as with and was returned to normal levels plasma levels with hepatic CTα activity We to plasma VLDL and HDL levels reduced in CTα knock-out mice. The experiments demonstrate that VLDL secretion and HDL in hepatocytes deficient in expression of CT by adenoviral delivery the PC in hepatocytes, lipid secretion was not However, in vivo of hepatic PC biosynthesis did lipoprotein levels, suggesting that of plasma be to of hepatic PC levels. VLDL in and M.E. J. Scopus Google the importance of has been that a deficient in choline hepatic in mice M. B. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar), Vance D.E. Biochem. Cell Biol. 1990; 68: PubMed Scopus Google Scholar), and in A.A. M. J. M.E. PubMed Google Scholar, K.A. J.T. A. J. PubMed Scopus Google Scholar). In the of plasma VLDL is reduced by a which partially, for the hepatic lipid K.A. J.T. A. J. PubMed Scopus Google Scholar). The role of PC biosynthesis in VLDL secretion from hepatocytes has been in our with medium deficient in and not choline A. Vance D.E. Vance J.E. J. Biol. 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We that plasma and decreased in the CTα knock-out mouse (6Jacobs R.L. Devlin C. Tabas I. Vance D.E. J. Biol. Chem. 2004; 279: 47402-47410Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). we that VLDL secretion is in CTα knock-out VLDL secretion by choline is Vance D.E. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar, Vance D.E. Biochem. J. PubMed Scopus Google Scholar, Vance D.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Z. Vance D.E. Biochim. Biophys. Acta. PubMed Scopus Google Scholar), we that knock-out hepatocytes with also lipoprotein adenoviral of CT in knock-out hepatocytes did not increase VLDL even though PC biosynthesis was normal levels. observations that than decreased PC in VLDL secretion in knock-out this were the is also that expression of CT did not these to be in vivo this in the hepatocytes, adenoviral expression of CT in knock-out mice hepatic PC levels. However, in this VLDL levels returned to levels, and the of plasma with hepatic CT is that the of VLDL an the increase in CTα that was not in primary hepatocytes, of the of these in the in vivo and hepatocyte experiments is the of CT activity by adenoviral CT activity returned to normal of whereas of the in hepatocyte medium in a increase in CT activity not is that levels of CT VLDL secretion from The of CT to secretion in wild type primary hepatocytes and was and was VLDL secretion is in with PEMT (15Noga A.A. Zhao Y. Vance D.E. J. Biol. Chem. 2002; 277: 42358-42365Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). When CTα was into CT activity was by whereas and into PC was and cellular PC was of a increase in PC C.J. Kalmar G.B. Cornell R.B. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of CT did not PC levels in C. Biochem. Biophys. 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