Choline Redistribution during Adaptation to Choline Deprivation

Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of phosphatidylcholine synthesized in the liver by the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Complete choline deprivation is achieved by feeding Pemt–/– mice a choline-deficient diet and is lethal due to liver failure. Mice that lack both PEMT and MDR2 (multiple drug-resistant protein 2) successfully adapt to choline deprivation via hepatic choline recycling. We now report another mechanism involved in this adaptation, choline redistribution. Normal levels of choline-containing metabolites were maintained in the brains of choline-deficient Mdr2–/–/Pemt–/– mice for 90 days despite continued choline consumption via oxidation. Choline oxidase activity had not been previously detected in the brain. Plasma levels of choline were also maintained for 90 days, whereas plasma phosphatidylcholine levels decreased by >60%. The injection of [3H]choline into Mdr2–/–/Pemt–/– mice revealed a redistribution of choline among tissues. Although CD-Pemt–/– mice failed to adapt to choline deprivation, choline redistribution was also initiated in these mice. The data suggest that adaptation to choline deprivation is not restricted to liver via choline recycling but also occurs in the whole animal via choline redistribution. Choline is an important nutrient for mammals. Choline can also be generated by the catabolism of phosphatidylcholine synthesized in the liver by the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase (PEMT). Complete choline deprivation is achieved by feeding Pemt–/– mice a choline-deficient diet and is lethal due to liver failure. Mice that lack both PEMT and MDR2 (multiple drug-resistant protein 2) successfully adapt to choline deprivation via hepatic choline recycling. We now report another mechanism involved in this adaptation, choline redistribution. Normal levels of choline-containing metabolites were maintained in the brains of choline-deficient Mdr2–/–/Pemt–/– mice for 90 days despite continued choline consumption via oxidation. Choline oxidase activity had not been previously detected in the brain. Plasma levels of choline were also maintained for 90 days, whereas plasma phosphatidylcholine levels decreased by >60%. The injection of [3H]choline into Mdr2–/–/Pemt–/– mice revealed a redistribution of choline among tissues. Although CD-Pemt–/– mice failed to adapt to choline deprivation, choline redistribution was also initiated in these mice. The data suggest that adaptation to choline deprivation is not restricted to liver via choline recycling but also occurs in the whole animal via choline redistribution. Choline is an important nutrient for humans and animals (1Best C.H. Huntsman M.E. J. Physiol. (Lond.). 1932; 75: 405-412Crossref Scopus (86) Google Scholar, 2Zeisel S.H. Nutrition. 2000; 16: 669-671Crossref PubMed Scopus (248) Google Scholar, 3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Choline is obtained either from the diet or from the catabolism of phosphatidylcholine (PC). 2The abbreviations used are: PC, phosphatidylcholine; PEMT, phosphatidylethanolamine N-methyltransferase; CD, choline-deficient; CS, choline-supplemented; CHT, choline high affinity transporter. PC is made from choline via the cytidine diphosphocholine pathway (4Kennedy E.P. Can. J. Biochem. Physiol. 1956; 34: 334-348Crossref PubMed Scopus (27) Google Scholar, 5Kennedy E.P. Weiss S.B. J. Biol. Chem. 1956; 222: 193-214Abstract Full Text PDF PubMed Google Scholar) and in hepatocytes, PC can also be made via the methylation of phosphatidylethanolamine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). Production of PC from the PEMT pathway followed by PC catabolism is the only known endogenous pathway for choline biosynthesis in animals. Complete choline deprivation can be achieved by feeding Pemt–/– mice a choline-deficient (CD) diet, and this results in rapid liver failure and lethality (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 6Walkey 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). In most mammalian cells, PC is used for the maintenance of membranes and as a precursor of signaling molecules. Hepatic PC is also required for very low density lipoprotein secretion (7Vance J.E. Vance D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins, and Membranes. Elsevier, New York2002: 505-526Google Scholar, 8Yao Z.M. Vance D.E. J. Biol. Chem. 1988; 263: 2998-3004Abstract Full Text PDF PubMed Google Scholar) and is an important component of bile. PC is transferred into the lumen of bile canaliculi via the action of MDR2/ABCB4 (9Smit J.J. Schinkel A.H. Oude Elferink R.P. Groen A.K. Wagenaar E. van Deemter L. Mol C.A. Ottenhoff R. van der Lugt N.M. van Roon M.A. van der Valk M.A. Offerhaus G.J.A. Berns A.J.M. Borst P. Cell. 1993; 75: 451-462Abstract Full Text PDF PubMed Scopus (1336) Google Scholar). We reasoned that, if biliary secretion of PC were blocked in Pemt–/– mice, the severe consequences of choline deprivation might be attenuated. Indeed, Mdr2–/–/Pemt–/– mice showed an adaptive response to choline deprivation, choline recycling in the liver, that permitted the mice to survive for at least 90 days (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Although the level of total choline-containing metabolites in the liver decreased by ∼50% after 21 days in Mdr2–/–/ Pemt–/– mice fed a CD diet compared with choline-supplemented (CS) mice, this level of total choline-containing metabolites was maintained for at least 3 months aided by choline recycling and by decreased choline oxidation (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Choline oxidation (the only catabolic pathway of choline) in the liver was not completely eliminated but continued at a low rate in CD-Mdr2–/–/Pemt–/– mice during prolonged choline deprivation (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). We, therefore, considered the possibility that choline is redistributed from non-hepatic tissues to the liver as another mechanism for adaptation to choline deprivation in Mdr2–/–/ Pemt–/– mice. During choline deprivation, no obvious phenotype was observed in organs other than liver in CD-Pemt–/– mice (6Walkey 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). The brain is an important organ for choline metabolism, because choline is required for biosynthesis of acetylcholine for neurotransmission as well as for the biosynthesis of PC (10Zeisel S.H. J. Am. Coll. Nutr. 2004; 23: 621S-626SCrossref PubMed Scopus (128) Google Scholar). Interestingly, the brains in both CD-Pemt–/– and -Mdr2–/–/Pemt–/– mice did not show any obvious damage during choline deprivation. Because the brain also appears to adapt to choline deprivation, we hypothesized that the brain obtains choline from peripheral tissues during choline deprivation. We, therefore, tested the hypothesis that, during severe choline deprivation, a mechanism is triggered whereby a redistribution of choline from other tissues to liver and brain allows these organs to maintain sufficient levels of choline/PC. Our results demonstrate that adaptation to choline deprivation is not restricted to the liver via choline recycling but also involves the whole body via choline redistribution among tissues. Animals, Lipid Analysis, and Choline Oxidase Assay—As in previous studies (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 11Li Z. Agellon L.B. Allen T.M. Umeda M. Jewell L. Mason A. Vance D.E. Cell Metab. 2006; 3: 321-331Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar), Mdr2–/–/Pemt–/– mice were produced by breeding Pemt–/– mice (C57BL/6; 129/J background) (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) with Mdr2–/– mice (FVB; 129/J background) (9Smit J.J. Schinkel A.H. Oude Elferink R.P. Groen A.K. Wagenaar E. van Deemter L. Mol C.A. Ottenhoff R. van der Lugt N.M. van Roon M.A. van der Valk M.A. Offerhaus G.J.A. Berns A.J.M. Borst P. Cell. 1993; 75: 451-462Abstract Full Text PDF PubMed Scopus (1336) Google Scholar). The mice were fed a CD diet (ICN, catalog number 0290138710) or a CS diet (the CD diet supplemented with 0.4% (w/w) choline chloride). All mice were fed the chow diet for 10–12 weeks, after which the Pemt–/– and Mdr2–/–/Pemt–/– mice were fed the CS diet for 24 h and then fed the CD diet for 3, 21, or 90 days. All mice were fasted for 12 h before sacrifice. Six to eight mice were used for each time point in each experiment, and assays were performed in duplicate. All data are means ± S.D. Lipid analyses (13Bligh E.G. Dyer W.J. Can. J. Biochem. Physiol. 1959; 37: 911-917Crossref PubMed Scopus (43132) Google Scholar, 14McCluer R.H. Ullman M.D. Jungalwala F.B. Adv. Chromatogr. 1986; 25: 309-353PubMed Google Scholar) and choline oxidase assays (15Pelech S.L. Pritchard P.H. Vance D.E. J. Biol. Chem. 1981; 256: 8283-8286Abstract Full Text PDF PubMed Google Scholar, 16Hise M.K. Mansbach II, C.M. Anal. Biochem. 1983; 135: 78-82Crossref PubMed Scopus (21) Google Scholar) were performed as previously described (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Plasma S100β Protein Assay—S100β is a protein in brain and, when found in the plasma, is a marker of brain damage (17Biberthaler P. Mussack T. Wiedemann E. Kanz K.G. Koelsch M. Gippner-Steppert C. Jochum M. World J. Surg. 2001; 25: 93-97Crossref PubMed Scopus (79) Google Scholar, 18Mussack T. Biberthaler P. Kanz K.G. Heckl U. Gruber R. Linsenmaier U. Mutschler W. Jochum M. Shock. 2002; 18: 395-400Crossref PubMed Scopus (68) Google Scholar). Sandwich enzyme-linked immunosorbent assay was performed for measurement of the level of S100β protein in 20 μl of plasma using rabbit polyclonal anti-S100β protein antibodies (Santa Cruz Biotechnology). The secondary antibody was anti-rabbit IgG-conjugated to horseradish peroxidase, and 3,3′,5,5′-tetramethylbenzidine (Sigma) was used for color development. Mouse brain were used as a for the measurement of Plasma from mice was used as a of and brain were for choline-containing metabolites PC, and choline with a the of choline by and choline oxidation by choline oxidase (15Pelech S.L. Pritchard P.H. Vance D.E. J. Biol. Chem. 1981; 256: 8283-8286Abstract Full Text PDF PubMed Google Scholar, 16Hise M.K. Mansbach II, C.M. Anal. Biochem. 1983; 135: 78-82Crossref PubMed Scopus (21) Google Scholar). for Choline and Choline from liver and brain were by and with antibodies (Santa Cruz or oxidase antibodies from of S100β protein was as a for brain Protein was as a for hepatic In of and Mdr2–/–/Pemt–/– mice were fed a CS diet or a CD diet for 3 or 21 days. in μl of was into mice via the Mice were h or 24 h after was by Plasma was by of whole at for 20 in a liver, and were and in and then at before were with a in of and catalog number in the whole tissues of liver, and as well as plasma was was to the of mice A. L. J. 2005; PubMed Scopus Google Scholar). plasma was as in a R. The Mouse in New Scholar). mice were in each and [3H]choline was in duplicate. was by and then by a (15Pelech S.L. Pritchard P.H. Vance D.E. J. Biol. Chem. 1981; 256: 8283-8286Abstract Full Text PDF PubMed Google Scholar, 16Hise M.K. Mansbach II, C.M. Anal. Biochem. 1983; 135: 78-82Crossref PubMed Scopus (21) Google Scholar). from mice were to a of 20 body for during Choline brain protein when found in the plasma, is a marker of brain damage (17Biberthaler P. Mussack T. Wiedemann E. Kanz K.G. Koelsch M. Gippner-Steppert C. Jochum M. World J. Surg. 2001; 25: 93-97Crossref PubMed Scopus (79) Google Scholar, 18Mussack T. Biberthaler P. Kanz K.G. Heckl U. Gruber R. Linsenmaier U. Mutschler W. Jochum M. Shock. 2002; 18: 395-400Crossref PubMed Scopus (68) Google Scholar). S100β was not detected in the plasma of and CD-Pemt–/– mice or in and CD-Mdr2–/–/Pemt–/– mice, a lack of brain damage in both CD-Pemt–/– mice and CD-Mdr2–/–/Pemt–/– mice level in brain color as a no S100β was detected in plasma of mice as a We also in the brains and did not any that choline deprivation did not in the brains of either Choline level of choline-containing metabolites in brain was Choline deprivation did not the total of choline-containing metabolites in the brains of either Pemt–/– mice or Mdr2–/–/Pemt–/– mice the of PC, the choline-containing was not in the brains of either during choline deprivation Interestingly, the brain maintained choline oxidation in both during choline deprivation, to both in and in assays Choline oxidase activity was by of [3H]choline with from the brains of Pemt–/– and Mdr2–/–/Pemt–/– mice fed the CS or CD diet in choline oxidase activity was observed in either after 3 or 21 days of the CD for the Mdr2–/–/Pemt–/– mice, after 90 days the CD diet, choline oxidase activity by an measurement of choline we both of mice that had been fed the CS or CD diet with of and 24 the mice were and the of was were observed the Pemt–/– mice fed the CD CS diet In in Mdr2–/–/Pemt–/– mice fed the CD diet for 21 days, the of in the brain was that in CS Mdr2–/–/Pemt–/– mice 24 of the had been choline oxidase activity in the we were to the protein in the brains of the mice by not the of choline oxidase protein in the to be in CD-Pemt–/– mice than in mice whereas hepatic protein levels of choline oxidase only decreased in Mdr2–/–/Pemt–/– mice at 21 days of choline deprivation compared with CS mice Choline oxidation is the only known catabolic pathway for choline (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, D.E. Vance D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins, and Membranes. Elsevier, New York2002: Scholar). this is the report that brain choline oxidase oxidation in the brain is maintained during choline deprivation. Pemt–/– and Mdr2–/–/Pemt–/– mice were fed the CS diet for 24 h and then fed the CD diet for 3, 21, or 90 days. Choline oxidase activity was by of [3H]choline with from brain after at for was by are ± S.D. from mice. Pemt–/– and Mdr2–/–/Pemt–/– mice were fed the CS diet for 24 h (CS) and then fed the CD diet for 3 or 21 days. of [3H]choline in μl of was into mice via the and mice were after or 24 in in the brain was The of was as a of total in choline metabolites in the brain. are to a and are ± S.D. from mice. for h 24 for CS the mice were fed as described for C. is a of choline oxidase from the of Pemt–/– and Mdr2–/–/Pemt–/– mice. results were obtained in from mice of each each protein choline an important in choline and is also a in choline Allen 2002; PubMed Scopus Google Scholar). The in 3 show that the of in brains was by choline deprivation whereas was a in in the of Mdr2–/–/Pemt–/– mice during choline deprivation. is by the of which is the of total choline-containing metabolites in brain M. 2005; PubMed Scopus Google Scholar). protein levels might from choline-containing metabolites in brain during choline deprivation. that the plasma level of choline did not during choline deprivation in either of mice, the level of plasma PC decreased from the data in and appears that the brains of both were to sufficient choline to maintain during choline deprivation. Choline and during Choline did not to the redistribution of choline from to we obtained the of choline the body by a of [3H]choline into the mice. the of choline during choline deprivation, [3H]choline was the into Pemt–/– mice or Mdr2–/–/Pemt–/– mice that had been fed the CS or CD time and 24 were used to choline of tissues after in each was the of a with a body of 20 The liver is the organ for choline oxidation E. 1959; Google Scholar). We previously that, during choline deprivation, the activity of hepatic choline oxidase is completely in both (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). the biliary PC secretion is in CD-Pemt–/– mice after 3 days and, of is in the Mdr2–/–/Pemt–/– mice. Because these are the for of choline from mice, we that choline was in CD mice as a mechanism for choline because choline is CS and CD mice, we can only the of choline if we to choline redistribution in CS and CD mice. In mice, and 24 h after [3H]choline the liver and and of the In the of in and plasma by and in other tissues did not and 24 h after [3H]choline injection Pemt–/– mice were fed the CD diet, the of in the and decreased by and and 24 h after injection of the in the liver, and by and of choline metabolites in mice and 24 h after [3H]choline the liver, and and of the whereas the of the plasma, and by and the Mdr2–/–/Pemt–/– mice were fed the CD diet, the of the and was decreased by and during the of of the liver, and by and The total of in tissues did not in and CD-Pemt–/– mice and 24 h after [3H]choline injection In in Mdr2–/–/Pemt–/– mice, the total in tissues was in mice fed the CS diet than in mice fed the CD the decreased from to 24 h after [3H]choline injection in but not in CD-Mdr2–/–/Pemt–/– mice suggest that the total of choline was maintained in the CD-Mdr2–/–/Pemt–/– mice and was maintained to an than in CD-Pemt–/– mice, because total in CD-Mdr2–/–/Pemt–/– mice was that in CD-Pemt–/– mice data the that, and 24 choline or of metabolites was redistributed among tissues of the CD and CS mice of both were the liver to be the of choline in CS mice but an of choline in CD mice. In mice, the brain was a of choline during choline deprivation. we found that body whereas liver in Mdr2–/–/Pemt–/– mice fed the CD in a in during choline deprivation. the of tissues decreased after 21 or 90 days of choline deprivation. results the that mice might tissues to choline to liver and brain. a redistribution of choline be for mice during choline and liver of Mdr2–/–/Pemt–/– ± ± ± ± ± ± ± were for CS CD ± ± ± ± were for CS CD ± were for CS CD ± ± ± ± were for CS CD mice. in a Choline well maintained level of total choline-containing metabolites in the liver and brain of CD-Mdr2–/–/Pemt–/– mice and the continued consumption of choline by oxidation 21 and 90 days of feeding the CD diet suggest that the liver and brain choline from other We choline redistribution in the mice by injection of [3H]choline into and CD-Pemt–/– or Mdr2–/–/Pemt–/– mice. The of and 24 h after injection of [3H]choline which tissues in choline redistribution. The results not of choline or as for the observed of and show that the liver is a of choline in CS Pemt–/– mice but a of choline in CD Pemt–/– mice. The data suggest that redistribution of choline from and to liver occurs during choline deprivation In Mdr2–/–/Pemt–/– mice, choline was redistributed from and to liver, and during choline deprivation. Interestingly, both CD showed that choline is redistributed from to brain and The in choline redistribution the during choline deprivation is that the is a of choline in Mdr2–/–/Pemt–/– mice but not in Pemt–/– mice. the choline redistribution in the CD-Pemt–/– mice, these mice of liver failure after 3 days. that the of choline this was not sufficient to these mice. We that, as a mechanism of adaptation to choline deprivation, choline redistribution also in animals in the We the possibility that tissues that we did not as either or of choline during choline deprivation. we this to be because choline as are and the of metabolites is to be very The of Choline via Choline level of total choline-containing metabolites in the brain did not during choline deprivation in either of the as we previously the level of total choline-containing metabolites in the liver decreased by ∼50% (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) and the level of PC in the plasma decreased by during choline deprivation in both (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). a decreased level of total choline-containing metabolites in the liver, but not in other during choline deprivation that the liver is the organ that is the most to the of choline deprivation. the liver is the only organ that of choline that be to other organs via lipoprotein (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, J.E. Vance D.E. Nutr. PubMed Scopus Google Scholar). The brain maintained activity of choline oxidase for 21 days 2) whereas the liver decreased choline oxidase in both during choline deprivation (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Our data suggest that the brain an of choline during the whole of choline deprivation. during the of choline deprivation in CD-Mdr2–/–/Pemt–/– mice liver as a of choline because the total choline level decreased before 21 days. In the liver an of choline during the of choline deprivation days or in CD-Mdr2–/–/Pemt–/– mice. choline redistribution among tissues during of choline deprivation. we found the of CD-Mdr2–/–/Pemt–/– mice for at least 90 days the maintenance of the level of total choline-containing metabolites in liver (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). was not that choline was into the liver to maintain a level of choline in these mice. The of Choline to the brain maintain a level of total choline during choline in we found that choline in the brain for only a of total choline in the whole body and In choline oxidase was in the brain of both during choline deprivation choline deprivation did not the total level of choline-containing metabolites in the brains of either of mice results suggest that choline deprivation not choline in the brain in either the brain obtained a of choline from peripheral tissues during choline deprivation. during choline deprivation, choline redistribution was which a of choline to the brain. choline in the plasma and levels of the high affinity choline a level of total choline-containing metabolites in the brain during choline redistribution 3 and studies that is in in a CD S.H. J. PubMed Scopus Google Scholar). that choline is an component for brain. in the brain did not choline in Pemt–/– mice or during choline deprivation CD-Pemt–/– mice of severe liver failure during choline deprivation (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 6Walkey 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). results that, when mice the of choline deprivation, a mechanism is triggered to important organs as brain and from choline deprivation, whereas other tissues as and choline to the brain and liver via choline redistribution. Choline Oxidase in the we report for the time the of choline oxidase activity in the brain. The activity of choline oxidase activity in brain was of that in the liver (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). liver, the brain of and be of to in which of the brain choline oxidase is of choline oxidase as in brains and (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) were not with the protein levels of choline oxidase as by is that the activity of choline oxidase is not only at the level but also In we the possibility that other of choline were and not by the antibody we In the a of choline oxidase might with to in the brain. was that choline oxidase activity in the brain was maintained to 21 days of choline in the Mdr2–/–/Pemt–/– mice, the of and possibility is that the of choline oxidase is not in the of we that the might of Choline observed that with the time of choline deprivation, the body of Mdr2–/–/Pemt–/– mice whereas liver the of tissues decreased after 21 days of choline deprivation. results the that these mice might tissues to choline of the liver and brain. redistribution of choline be for mice during choline deprivation. is known choline in the of choline was observed in the in both both that choline a in mice from the lumen and of which PC is an The mechanism by which choline redistribution occurs is also an that choline deprivation did not the of choline in plasma but the of plasma PC in Pemt–/– mice after 3 days. choline deprivation, the liver PC than Plasma PC is with high density and the liver is the for of high density lipoprotein C.J. Vance D.E. Vance J.E. Biochemistry of Lipids, Lipoproteins, and Membranes. Elsevier, New York2002: Scholar). the of plasma PC by the liver is from high density lipoprotein decreased high density by CD-Pemt–/– compared with Z. Agellon L.B. Allen T.M. Umeda M. Jewell L. Mason A. Vance D.E. Cell Metab. 2006; 3: 321-331Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar) might failure to adapt to choline deprivation. Although plasma choline can be a for the cytidine diphosphocholine pathway in liver, the of choline activity in the of CD-Pemt–/– mice might this possibility (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). in CD-Mdr2–/–/Pemt–/– mice, choline levels in plasma and activity of choline (3Li Z. Agellon L.B. Vance D.E. J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) might that the choline the cytidine diphosphocholine plasma choline appears to a in choline redistribution. We for Vance for the and of for the choline oxidase

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