Physiological consequences of disruption of mammalian phospholipid biosynthetic genes

By 1959, Eugene Kennedy and coworkers had outlined most pathways of phospholipid biosynthesis. In the next four decades, the emphasis was on enzymology and regulation of these pathways. In the last 12 years, several lines of mice with disrupted genes of phospholipid biosynthesis were generated. From this research, we have learned that embryonic lethality occurs in mice that lack choline kinase (CK) α, CTP:phosphocholine cytidylyltransferase α, CTP:phosphoethanolamine cytidylyltransferase, or phosphatidylserine decarboxylase. Whereas mice that lack CK β are viable but develop hindlimb muscular dystrophy and neonatal bone deformity. Mice that lack CTP:phosphocholine cytidylytransferase β have gonadal dysfunction and defective axon branching. Mice that lack phosphatidylethanolamine N-methyltransferase exhibit no phenotype until fed a choline-deficient diet, which leads to rapid liver failure. Future research should extend our knowledge about the function of these and other enzymes of phospholipid biosynthesis. By 1959, Eugene Kennedy and coworkers had outlined most pathways of phospholipid biosynthesis. In the next four decades, the emphasis was on enzymology and regulation of these pathways. In the last 12 years, several lines of mice with disrupted genes of phospholipid biosynthesis were generated. From this research, we have learned that embryonic lethality occurs in mice that lack choline kinase (CK) α, CTP:phosphocholine cytidylyltransferase α, CTP:phosphoethanolamine cytidylyltransferase, or phosphatidylserine decarboxylase. Whereas mice that lack CK β are viable but develop hindlimb muscular dystrophy and neonatal bone deformity. Mice that lack CTP:phosphocholine cytidylytransferase β have gonadal dysfunction and defective axon branching. Mice that lack phosphatidylethanolamine N-methyltransferase exhibit no phenotype until fed a choline-deficient diet, which leads to rapid liver failure. Future research should extend our knowledge about the function of these and other enzymes of phospholipid biosynthesis. In 1959, the general outline of biosynthesis of major phospholipids had been established in studies pioneered by Eugene Kennedy (1Kennedy E.P. Weiss S.B. The function of cytidine coenzymes in the biosynthesis of phospholipides.J. Biol. Chem. 1956; 222: 193-214Abstract Full Text PDF PubMed Google Scholar, 2Kennedy E.P. Metabolism of lipides.Annu. Rev. Biochem. 1957; 26: 119-148Crossref PubMed Scopus (154) Google Scholar, 3Kennedy E.P. Discovery of the pathways for the biosynthesis of phosphatidylcholine. In Phosphatidylcholine Metabolism. D. E. Vance. CRC Press, Boca Raton, FL1989: 1-9Google Scholar). A key finding was that CTP, not ATP, was the ribonucleoside triphosphate required for phospholipid biosynthesis (1Kennedy E.P. Weiss S.B. The function of cytidine coenzymes in the biosynthesis of phospholipides.J. Biol. Chem. 1956; 222: 193-214Abstract Full Text PDF PubMed Google Scholar). The next major focus was to purify enzymes involved in phospholipid biosynthesis, many of which were integral membrane proteins. Thus, success was limited. Choline kinase (CK) was purified in 1984 (4Ishidate K. Nakagomi K. Nakazawa Y. Complete purification of choline kinase from rat kidney and preparation of rabbit antibody against rat kidney choline kinase.J. Biol. Chem. 1984; 259: 14706-14710Abstract Full Text PDF PubMed Google Scholar), CTP:phosphocholine cytidylyltransferase (CT) was purified in 1987 (5Feldman D.A. Weinhold P.A. CTP:phosphorylcholine cytidylyltransferase from rat liver. Isolation and characterization of the catalytic subunit.J. Biol. Chem. 1987; 262: 9075-9081Abstract Full Text PDF PubMed Google Scholar), and the integral membrane protein, phosphatidylethanolamine (PE) N-methyltransferase (PEMT) that converts PE to PC was purified in 1987 (6Ridgway N.D. Vance D.E. Purification of phosphatidylethanolamine N-methyltransferase from rat liver.J. Biol. Chem. 1987; 262: 17231-17239Abstract Full Text PDF PubMed Google Scholar). Several phospholipid biosynthetic enzymes have never been purified. In the 1970s, investigations into the regulation of phospholipid biosynthesis were initiated. In 1975, primary rat hepatocytes were used to demonstrate that the second enzyme in the Kennedy pathway for PC biosynthesis, CT, catalyzed the rate-limiting step (7Sundler R. Akesson B. Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates.J. Biol. Chem. 1975; 250: 3359-3367Abstract Full Text PDF PubMed Google Scholar). These findings were confirmed under most metabolic conditions (8Vance D.E. Choy P.C. How is phosphatidylcholine biosynthesis regulated?.Trends in Bioch. Sci. 1979; 4: 145-148Abstract Full Text PDF Scopus (110) Google Scholar). In addition, the rate-limiting enzyme of PE synthesis via CDP-ethanolamine was identified as CTP:phosphoethanolamine cytidylyltransferase (ET) (7Sundler R. Akesson B. Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates.J. Biol. Chem. 1975; 250: 3359-3367Abstract Full Text PDF PubMed Google Scholar). A striking regulatory feature of PC biosynthesis is that CT is inactive in the cytosolic fraction of cells but is activated by translocation to membranes (9Vance D.E. Pelech S.L. Enzyme translocation in the regulation of phosphatidylcholine biosynthesis.Trends Biochem. Sci. 1984; 9: 17-20Abstract Full Text PDF Scopus (101) Google Scholar). Insights into the mechanism of translocation of CT to membranes have been largely provided by Cornell and Northwood (10Cornell R.B. Northwood I.C. Regulation of CTP:phosphocholine cytidylyltransferase by amphitropism and relocalization.Trends Biochem. Sci. 2000; 25: 441-447Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar) and Taneva et al. (11Taneva S. Dennis M.K. Ding Z. Smith J.L. Cornell R.B. Contribution of each membrane binding domain of the CTP:Phosphocholine cytidylyltransferase-alpha dimer to its activation, membrane binding, and membrane cross-bridging.J. Biol. Chem. 2008; 283: 28137-28148Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Studies on regulation of expression of mRNAs encoding CTα have concluded that CTα expression is linked to the cell cycle, cell growth, and differentiation rather than energy metabolism (12Sugimoto H. Banchio C. Vance D.E. Transcriptional regulation of phosphatidylcholine biosynthesis.Prog. Lipid Res. 2008; 47: 204-220Crossref PubMed Scopus (52) Google Scholar). Clearly, significant progress has been made during the last 50 years in understanding the enzymology and regulation of PC biosynthesis. Moreover, some progress was made in understanding the enzymology and regulation of the biosynthesis of other phospholipids. The intent of this article is to focus on physiological consequences of deletion of genes of phospholipid metabolism in mice that have been generated in the last 12 years. PEMT converts PE to PC in three sequential methylation reactions that use S-adenosylmethionine as methyl group donor (Fig. 1). PEMT is expressed mainly in liver (13Vance D.E. Ridgway N.D. The methylation of phosphatidylethanolamine.Prog. Lipid Res. 1988; 27: 61-79Crossref PubMed Scopus (201) Google Scholar) and produces ∼30% of hepatic PC, whereas the CDP-choline pathway produces 70% of PC (7Sundler R. Akesson B. Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates.J. Biol. Chem. 1975; 250: 3359-3367Abstract Full Text PDF PubMed Google Scholar). The mouse gene encoding PEMT (Pemt) was disrupted (14Walkey C.J. Donohue L.R. Bronson R. Agellon L.B. Vance D.E. Disruption of the murine gene encoding phosphatidylethanolamine N-methyltransferase.Proc. Natl. Acad. Sci. USA. 1997; 94: 12880-12885Crossref PubMed Scopus (139) Google Scholar). Pemt−/− mice that were fed chow exhibited no obvious phenotype. When Pemt−/− mice were fed a choline-deficient (CD) diet, the concentration of hepatic PC in Pemt−/− mice was ∼50% lower than in Pemt+/+ mice and liver failure occurred after 3 days (15Walkey C.J. Yu L. Agellon L.B. Vance D.E. Biochemical and evolutionary significance of phospholipid methylation.J. Biol. Chem. 1998; 273: 27043-27046Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Thus, PEMT appears to have survived during evolution to provide PC/choline when dietary choline is inadequate. The mechanism responsible for the dramatic loss of hepatic PC, and how this led to liver failure, has been elucidated. The liver secretes lipoproteins and bile, both of which contain significant amounts of PC. Thus, there is a tremendous drain of PC from the liver into bile. Hence, it was postulated that when PC biosynthesis was attenuated by simultaneous lack of PEMT and dietary choline, the amount of PC secreted into bile might not be replaced by new synthesis. To test this hypothesis, Pemt−/− mice were bred with a mouse in which the PC flippase (Mdr2) on the bile canalicular membrane was eliminated and PC secretion into bile was prevented (16Smit J.J. Schinkel A.H. Elferink R.P. Oude Groen A.K. Wagenaar E. Deemter L.van Mol C.A. Ottenhoff R. Lugt N.M. van der Roon M.A. van al et Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.Cell. 1993; 75: 451-462Abstract Full Text PDF PubMed Scopus (1336) Google Scholar). The Mdr2−/− mice and the double knockout mice were fed the CD diet. The rapid decrease in PC that occurred in livers of Pemt−/− mice was attenuated in Pemt−/−/Mdr2−/− mice (17Li Z. Agellon L.B. Vance D.E. Phosphatidylcholine homeostasis and liver failure.J. Biol. Chem. 2005; 280: 37798-37802Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). These mice did not did not experience liver failure after 3 days of choline deficiency but instead lived for >90 days. Unexpectedly, the PC in livers of Pemt−/−/Mdr2−/− mice that had been fed the CD diet for 21 days was also 50% lower than in choline-supplemented mice. Clearly, the liver failure was not simply due to decreased hepatic PC. Moreover, liver failure could not be attributed to steatosis, because Pemt−/−/Mdr2−/− mice accumulated more hepatic triacylglycerol (TG) after 21 days of the CD diet than did Pemt−/− mice after 3 days. Thus, the mechanism that caused liver failure in Pemt−/− mice fed the CD diet was investigated (18Li Z. Agellon L.B. Allen T.M. Umeda M. Jewell L. Mason A. Vance D.E. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis.Cell Metab. 2006; 3: 321-331Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar). The conclusion was that a decreased molar ratio of PC/PE was responsible for development of steatohepatitis and liver failure. Thus, the PC/PE ratio in livers of Pemt−/− mice fed the CD diet was ∼0.8 compared with ∼1.8 for mice fed the choline-supplemented diet. These and other findings led to the hypothesis that some cell surface PC (a cylindrical molecule) in Pemt−/− hepatocytes was replaced by PE (an inverted cone-shaped molecule), resulting in imperfect packing of the plasma membrane bilayer so that molecules leaked through the plasma membrane and promoted inflammation associated with steatohepatitis. Subsequent studies substantiated the hypothesis (18Li Z. Agellon L.B. Allen T.M. Umeda M. Jewell L. Mason A. Vance D.E. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis.Cell Metab. 2006; 3: 321-331Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar). Thus, the PC/PE ratio appears to play a fundamental role in maintaining hepatocyte integrity. Whereas Pemt−/− mice do not exhibit an obvious phenotype when fed a chow diet, when challenged with a high-fat/high-cholesterol diet, the amount of TG and apolipoprotein (apo) B100 in plasma lipoproteins of male mice was less than in Pemt+/+ mice fed the same diet (19Noga A.A. Vance D.E. Insights into the requirement of phosphatidylcholine synthesis for liver function in mice.J. Lipid Res. 2003; 44: 1998-2005Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Noga A.A. Vance D.E. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice.J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). Subsequently, the lower levels of plasma TG and apo B100 were attributed to a reduced rate of hepatic VLDL secretion (19Noga A.A. Vance D.E. Insights into the requirement of phosphatidylcholine synthesis for liver function in mice.J. Lipid Res. 2003; 44: 1998-2005Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 20Noga A.A. Vance D.E. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice.J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). PC and cholesteryl ester in plasma of mice are mainly carried in HDLs. In Pemt−/− mice fed either chow or a high-fat/high-cholesterol diet, PC and cholesteryl in plasma were 25%–45% lower than in Pemt+/+ mice fed the same diet (20Noga A.A. Vance D.E. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice.J. Biol. Chem. 2003; 278: 21851-21859Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). The reduction in plasma lipids was due to increased expression of the scavenger receptor-B1 (21Robichaud J.C. Francis G.A. Vance D.E. A role for hepatic scavenger receptor class B, type I in decreasing high-density lipoprotein levels in mice that lack phosphatidylethanolamine N-methyltransferase.J. Biol. Chem. 2008; 283: 35496-35506Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The products of the PEMT reaction are PC and S-adenosylhomocysteine. For each molecule of PC generated, three S-adenosylhomocysteine molecules are formed, from which homocysteine is derived by hydrolysis. The level of homocysteine in plasma of Pemt−/− mice is 50% lower than in Pemt+/+ mice (22Noga A.A. Stead L.M. Zhao Y. Brosnan M.E. Brosnan J.T. Vance D.E. Plasma homocysteine is regulated by phospholipid methylation.J. Biol. Chem. 2003; 278: 5952-5955Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Furthermore, hepatic PEMT activity is 2-fold higher in liver-specific CTα knockout mice than in wild-type mice, and the plasma homocysteine level is 20–40% higher (23Jacobs R.L. Stead L.M. Devlin C. Tabas I. Brosnan M.E. Brosnan J.T. Vance D.E. Physiological regulation of phospholipid methylation alters plasma homocysteine in mice.J. Biol. Chem. 2005; 280: 28299-28305Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). These and other studies suggest that PEMT generates ∼50% of homocysteine in plasma and have clinical relevance, because elevated plasma homocysteine is a risk factor for cardiovascular disease (24Refsum H. Ueland P.M. Nygard O. Vollset S.E. Homocysteine and cardiovascular disease.Annu. Rev. Med. 1998; 49: 31-62Crossref PubMed Scopus (1852) Google Scholar). CT is encoded by two genes, Pcyt1a and Pcyt1b. CTα (product of the Pcyt1a gene) is largely localized to the nucleus of many different cell types (25Wang Y. Sweizer T.D. Weinhold P.A. Kent C. Nuclear localization of soluble CTP:phosphocholine cytidylyltransferase.J. Biol. Chem. 1993; 268: 5899-5904Abstract Full Text PDF PubMed Google Scholar). Disruption of the Pcyt1a gene in mice resulted in early embryonic death (26Wang L. Magdaleno S. Tabas I. Jackowski S. embryonic lethality in mice with deletion of the CTP:phosphocholine cytidylyltransferase gene Biol. 2005; 25: PubMed Scopus Google Scholar). by is localized to the S. the from gene to Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). Mice two of and that are by of the D. P.M. C. B. Jackowski S. Tabas I. in CTP:phosphocholine are viable under conditions but are to Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The gene was disrupted in mice. Mice that lack but exhibit gonadal dysfunction S. K. M.A. Disruption of expression leads to gonadal Biol. PubMed Scopus Google Scholar). The major of expression of is the mice do not have obvious axon of from mice is L. and finding is with in which reduction of expression in cells by decreased by L. R.B. Vance D.E. Vance Phosphatidylcholine biosynthesis via CTP:phosphocholine cytidylyltransferase and Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). mice do not during the was used to CTα expression in several cell types in CT activity was decreased by D. P.M. C. B. Jackowski S. Tabas I. in CTP:phosphocholine are viable under conditions but are to Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). When CT activity is increased I. metabolism in 1997; PubMed Scopus Google Scholar). was postulated that increased CT activity PC synthesis and the from cell death by increased from the In of this hypothesis, of survived after with whereas of wild-type survived D. P.M. C. B. Jackowski S. Tabas I. in CTP:phosphocholine are viable under conditions but are to Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the secretion of and of CTα expression in mouse secretion of these whereas secretion of and apo was Y. C. A. L. E. K. E. Jackowski S. secretion phosphatidylcholine Biol. 2008; PubMed Scopus Google Scholar). appears that PC generated via CTα is required for secretion of these two The was also used to CTα in mouse mice are viable and R.L. Devlin C. Tabas I. Vance D.E. deletion of hepatic CTP:phosphocholine cytidylyltransferase a in mice plasma high density and very low density Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.L. S. Zhao Y. Francis G.A. Vance D.E. CTP:phosphocholine is a of plasma and Biol. 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The hindlimb muscular dystrophy in mice appears to be caused by attenuated PC biosynthesis and PC G.A. and cells have two major PE biosynthetic the CDP-ethanolamine pathway (1Kennedy E.P. Weiss S.B. The function of cytidine coenzymes in the biosynthesis of phospholipides.J. Biol. Chem. 1956; 222: 193-214Abstract Full Text PDF PubMed Google Scholar) on the and the pathway in Kennedy E.P. L. and of Biol. Chem. Full Text PDF Google Scholar) (Fig. 1). of the two pathways that of PE might be to biosynthetic The of the PE biosynthetic pathways in cells has not been in several cell of PE is made from as the major of phosphatidylethanolamine in Natl. Acad. Sci. USA. 1984; PubMed Scopus Google Scholar). genes kinase is a whereas the other is for A. M.A. Jackowski S. of a kinase the CDP-ethanolamine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). lines of mice have been generated with disruption of the In was reduced and of Y. C. Jackowski S. and death in mice in kinase Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In the and and were as was of embryonic and S.E. P.A. A.H. and in kinase 2008; PubMed Scopus Google Scholar). The for the two lines of knockout mice to be In to CT, is encoded by a A. A. L. M. and of the mouse and PubMed Scopus Google Scholar). mice were generated M. and metabolic of disruption of the mouse CTP:phosphoethanolamine cytidylyltransferase gene Biol. 27: PubMed Scopus Google Scholar). mice are and levels of PE are is for mouse because to embryonic Thus, PE from for PE made via activity in cells (Fig. is encoded by a PE synthesis from occurs in and the of to PE is regulated by of from the to translocation to the is an in Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). The and an domain membranes synthesis in a membrane fraction associated with Biol. Chem. Full Text PDF PubMed Google Scholar) PE is made in in by Vance that phosphatidylserine is into via a membrane and that the of phosphatidylethanolamine is derived from of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of in mice embryonic whereas mice embryonic and have of a in R. A. A. Vance Disruption of the phosphatidylserine gene in mice embryonic lethality and Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus (189) Google Scholar). is that is required to provide PE for function and Thus, of PE are to biosynthetic and both pathways of PE synthesis are for mouse Studies in cells that is by two (Fig. J.L. Isolation and characterization of a cell or phosphatidylserine for and defective phosphatidylserine Biol. Chem. Full Text PDF PubMed Google Scholar). for choline of PC, whereas with and are localized to and are largely from the of Vance and are localized to Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is expressed in mouse but is most expressed in R. B. D.A. Vance the of phosphatidylserine in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). mice are of male mice are than in wild-type and of are R. B. D.A. Vance the of phosphatidylserine in mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to reduction in activity by both and amounts of and PE are in and R. R. Vance homeostasis in phosphatidylserine 2006; PubMed Scopus Google Scholar). Thus, is not required for mouse and for the most for mice were generated and were also mice have a and and are D. R. Vance the of phosphatidylserine of mice.J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Thus, is not for mouse development or activity in was the of was not mice were bred with mice, as no double knockout mice were D. R. Vance the of phosphatidylserine of mice.J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus (63) Google Scholar). mice with three are viable some of activity and a reduction in of to Thus, mice as as of activity and reduced amounts of and but a of appears to be These studies significant in the two biosynthetic pathways. The evolutionary that expression of two Disruption of phospholipid biosynthetic genes in mice has our understanding of the physiological for phospholipids 1). gene not embryonic because phospholipids cell integrity. Several enzyme involved in the biosynthesis of PC, and are encoded by Whereas PEMT deficiency for the most by the CDP-choline and do not for of PE made by these pathways. lack of is not by whereas in most be replaced by Moreover, for and Thus, PE appears to have two biosynthetic consequences of gene in phospholipid muscular neonatal bone plasma to cell secretion of defective axon failure after 3 plasma decreased increased for these are in the high high are as used in in a new

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