Three Mammalian Lipins Act as Phosphatidate Phosphatases with Distinct Tissue Expression Patterns

We previously identified mutations in the Lpin1 gene, encoding lipin-1, as the underlying cause of lipodystrophy in the fatty liver dystrophy (fld) mutant mouse. Lipin-1 is normally expressed at high levels in adipose tissue and skeletal muscle, and deficiency in the fld mouse causes impaired adipose tissue development, insulin resistance, and altered energy expenditure. We also identified two additional lipin protein family members of unknown function, lipin-2 and lipin-3. Han et al. (Han, G. S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210–9218) recently demonstrated that the single lipin homolog in yeast, Smp2, exhibits phosphatidate phosphatase type-1 (PAP1) activity, which has a key role in glycerolipid synthesis. Here we demonstrate that lipin-1 accounts for all of the PAP1 activity in white and brown adipose tissue and skeletal muscle. However, livers of lipin-1-deficient mice exhibited normal PAP1 activity, indicating that other members of the lipin protein family could have PAP1 activity. Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity. Each of the three lipin family members showed Mg2+-dependent activity that was specific for phosphatidate under the conditions employed. The different lipins showed distinct tissue expression patterns. Our results establish the three mammalian lipin proteins as PAP1 enzymes and explain the biochemical basis for lipodystrophy in the lipin-1-deficient fld mouse. We previously identified mutations in the Lpin1 gene, encoding lipin-1, as the underlying cause of lipodystrophy in the fatty liver dystrophy (fld) mutant mouse. Lipin-1 is normally expressed at high levels in adipose tissue and skeletal muscle, and deficiency in the fld mouse causes impaired adipose tissue development, insulin resistance, and altered energy expenditure. We also identified two additional lipin protein family members of unknown function, lipin-2 and lipin-3. Han et al. (Han, G. S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210–9218) recently demonstrated that the single lipin homolog in yeast, Smp2, exhibits phosphatidate phosphatase type-1 (PAP1) activity, which has a key role in glycerolipid synthesis. Here we demonstrate that lipin-1 accounts for all of the PAP1 activity in white and brown adipose tissue and skeletal muscle. However, livers of lipin-1-deficient mice exhibited normal PAP1 activity, indicating that other members of the lipin protein family could have PAP1 activity. Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity. Each of the three lipin family members showed Mg2+-dependent activity that was specific for phosphatidate under the conditions employed. The different lipins showed distinct tissue expression patterns. Our results establish the three mammalian lipin proteins as PAP1 enzymes and explain the biochemical basis for lipodystrophy in the lipin-1-deficient fld mouse. Triacylglycerol (TAG) 3The abbreviations used are: TAG, triacylglycerol; C1P, ceramide 1-phosphate; DAG, diacylglycerol; LPP, lipid phosphate phosphatase (the NEM and Mg2+-insensitive PAP2 activities); NEM, N-ethylmaleimide; PA, phosphatidate; PAP1, Mg2+-dependent and NEM inhibitable phosphatidate phosphatases (lipins); PC, phosphatidylcholine; S1P, sphingosine 1-phosphate; wt, wild-type; RT, reverse transcription. plays a key role in metabolic homeostasis, serving as the major energy storage molecule that allows organisms to survive periods of food deprivation. The regulation of TAG storage is important in human disease because both excessive and inadequate fat storage is associated with dyslipidemia, insulin resistance, and diabetes (reviewed in Refs. 1Petersen K.F. Shulman G.I. Am. J. Med. 2006; 119: S10-S16Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar, 2Reue K. Phan J. Curr. Opin. Clin. Nutr. Metab. Care. 2006; 9: 436-441Crossref PubMed Scopus (38) Google Scholar, 3Hegele R.A. Pollex R.L. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005; 289: R663-R669Crossref PubMed Scopus (47) Google Scholar). We previously characterized the fatty liver dystrophy mouse, a model of generalized lipodystrophy with impaired TAG storage in adipose tissue, insulin resistance, and increased susceptibility to atherosclerosis (4Reue K. Xu P. Wang X.P. Slavin B.G. J. Lipid Res. 2000; 41: 1067-1076Abstract Full Text Full Text PDF PubMed Google Scholar, 5Reue K. Donkor J. Future Lipidol. 2006; 1: 91-101Crossref Google Scholar). Lipodystrophy in the fld mouse results from mutation in the Lpin1 (lipin-1) gene, the founding member of a family of three genes of previously unknown function (6Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar). Genes for lipin-1, lipin-2, and lipin-3 occur in mammals and other vertebrates, whereas a single lipin gene ortholog can be detected in evolutionarily distant organisms including fruit fly, nematode, plants, and yeast (6Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar). This suggests a fundamental function for lipin that is conserved from single celled eukaryotes to mammals. In the mouse, lipin-1 is expressed at high levels in adipose tissue and skeletal muscle, consistent with a role in lipid metabolism in these tissues. Indeed, adipocytes in lipin-1-deficient mice fail to accumulate TAG and do not develop mature adipocyte function (7Phan J. Peterfy M. Reue K. J. Biol. Chem. 2004; 279: 29558-29564Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). By contrast, transgenic mice with enhanced lipin-1 expression in adipocytes accumulate more TAG per cell and are prone to obesity (7Phan J. Peterfy M. Reue K. J. Biol. Chem. 2004; 279: 29558-29564Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 8Phan J. Reue K. Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 9Peterfy M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Furthermore, lipin-1 expression levels are reduced in adipose tissue of human lipodystrophic patients concomitantly with reduced fat mass (10Lindegaard B. Larsen L.F. Hansen A.B. Gerstoft J. Pedersen B.K. Reue K. Int. J. Obes. (Lond.). 2007; (in press)PubMed Google Scholar). A role for lipin-1 in muscle metabolism is suggested by increased energy expenditure and fatty acid oxidation in the muscle of lipin-1-deficient mice and the opposite effects in muscle-specific lipin-1 transgenic mice (8Phan J. Reue K. Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Thus, alterations in lipin-1 expression levels in either adipose tissue or skeletal muscle produce important physiological effects on energy storage and expenditure. In mammalian cells, the de novo biosynthesis of TAG, PC, and phosphatidylethanolamine is catalyzed mainly through the glycerol phosphate pathway (11Coleman R.A. Lewin T.M. Muoio D.M. Annu. Rev. Nutr. 2000; 20: 77-103Crossref PubMed Scopus (263) Google Scholar). Several enzymes in this pathway have been characterized, but not all of these have been identified at the molecular level. Among those for which a gene has not been isolated is the phosphatidate phosphohydrolase (phosphatase) type-1 that converts the PA formed from glycerol phosphate and lysoPA to DAG (12Brindley D.N. Phosphatidate Phosphohydrolase: Its Role in Glycerolipid Synthesis. CRC Press, Inc., Boca Raton, FL1988: 21-77Google Scholar). There are two main types of PA phosphatase. The first is the type-1 activity (PAP1) that is characterized by its inhibition by N-ethylmaleimide (NEM) and a complete dependence on Mg2+ (12Brindley D.N. Phosphatidate Phosphohydrolase: Its Role in Glycerolipid Synthesis. CRC Press, Inc., Boca Raton, FL1988: 21-77Google Scholar, 13Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar). In contrast, the second activity (PAP2) is neither inhibited by NEM nor is it stimulated by Mg2+. There are three PAP2 enzymes that are integral membrane proteins (14Brindley D.N. J. Cell. Biochem. 2004; 92: 900-912Crossref PubMed Scopus (186) Google Scholar). They catalyze the hydrolysis of a variety of lipid phosphate esters including lysoPA, C1P, S1P, and DAG pyrophosphate in addition to PA. Because of this and the uncertainty of the physiological substrates for these enzymes, the three PAP2 enzymes were renamed lipid phosphate phosphatases (LPPs) (15Brindley D.N. Waggoner D.W. J. Biol. Chem. 1998; 273: 24281-24284Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). These enzymes control signal transduction by the bioactive lipid phosphates compared with their dephosphorylated products (14Brindley D.N. J. Cell. Biochem. 2004; 92: 900-912Crossref PubMed Scopus (186) Google Scholar). The phenotype of the lipin-1-deficient fld mouse is consistent with a defect in TAG synthesis, raising the possibility that lipin-1 may perform a role in glycerolipid biosynthesis. Recently, Han et al. (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar) reported a breakthrough in the identification of the Mg2+-dependent PAP1 activity from Saccharomyces cerevisiae. Through protein sequencing, the yeast PAP1 is shown to be identical to Smp2, the yeast ortholog of mammalian lipin. Recombinant human lipin-1 expressed in Escherichia coli also shows PAP1 activity (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). However, the extrapolation of studies on yeast lipin to its role in mammals is complicated by the fact that mammals possess three lipin genes. Furthermore, of the mouse and human lipin-1 gene to two protein and which have distinct in adipocytes M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). the addition of to the to different expression adipocyte altered and in of gene expression adipocyte K. Donkor J. Future Lipidol. 2006; 1: 91-101Crossref Google Scholar, 9Peterfy M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Here we the fld mouse to establish the physiological role of lipin-1 as the PAP1 in adipose tissue and muscle, the biochemical basis for lipodystrophy in these We also that all mammalian lipin family members and PAP1 activity that is specific for The different lipins distinct tissue expression physiological for in glycerolipid synthesis. and mice were from the The were to mutant and for mice were mouse and were on a were in the first of the studies were under of the of Lipid with was as by Martin et al. A. Gómez-Muñoz A. Z. Brindley D.N. 1991; PubMed Scopus Google Scholar). lysoPA and were with and from that sphingosine and DAG from The were and as previously D.W. Gómez-Muñoz A. J. Brindley D.N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These were to of the to the specific by mouse tissue expression was from of three was isolated with and from of reverse was with the expression was to and in human was of first and and from a human adipose tissue are in for lipin-2, and were by of the and the expression the for and lipin-3 and the for for lipin were as lipin-2, expression were by used for are in Cell and were in and with at and were with the were and for PAP1 activity as of PAP1 and PAP2 were in PAP1 and phosphatase and were in the to which was to the and and complete of PAP1 activity. We showed previously that and PAP1 activity Brindley D.N. Biochem. J. PubMed Scopus Google Scholar). We for PAP1 fatty and PA with which was in and that was used to the lipid Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, A. Gómez-Muñoz A. Z. Brindley D.N. 1991; PubMed Scopus Google Scholar). was to the cell its in the was to were at with of as for of was to the PA and formed by A A. Gómez-Muñoz A. Z. Brindley D.N. 1991; PubMed Scopus Google Scholar). The were and of which the was and by by the and the of were that of the PA was the were from at three different protein to the of the The of the in the was to that from the phosphatase were as not to PAP1 activity. were in the of NEM to PAP1 and to for PAP2 activity in this This was normally of the activity from which it was to PAP1 activity. of the PAP1 for the different lipins was a model as by Han et al. (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). we used from the that were that the of in the was Each in a of fatty acid and the of PA DAG was as in the of NEM were from those in its to PAP1 activity. The of PAP1 for the was under these conditions that the PAP1 that of the phosphatase activity of PA was also compared that with of lysoPA, S1P, or activity was the of the as previously Xu J. J. Carman G.M. Waggoner D.W. Brindley D.N. Biochem. J. PubMed Scopus Google Scholar). of the PAP1 was the model Biochem. PubMed Scopus Google Scholar). were in the of a from PAP1 by with in in Xu J. J. Carman G.M. Waggoner D.W. Brindley D.N. Biochem. J. PubMed Scopus Google Scholar). The or and NEM was The of the and and of were as for in cell were the protein of protein were in and to a were with in and with mouse were for at with a of to at was detected with the and with tissue were from and fld tissue and detected with a the by and with enhanced the of Mg2+-dependent yeast protein a which a in a of Mg2+-dependent phosphatases (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, R.L. J. Biol. PubMed Scopus Google Scholar). This is also in lipin proteins from other including mouse and human not the previously (6Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar) and has the in lipin-1 in and The is also in mammalian lipin-2 and not that all lipin proteins may PAP1 activity. Lipin-1 for PAP1 in and impaired TAG storage in adipose tissue and muscle of lipin-1-deficient fld mice suggested that lipin-1 could be the PAP1 in these tissues. we from fld mice for PAP1 activity. a we also the activity, which is catalyzed by three enzymes that are in to the shown in PAP1 activity was detected in and white adipose tissue, in brown adipose tissue, or in skeletal muscle of the fld mouse compared with the from we additional activity in adipose tissue of the fld mice we used the PAP1 in the or of NEM and with reduced or Mg2+ not The specific activity cell of PAP1 was in white and brown adipose of the control mice compared with that in liver and muscle. activity was in from control and fld from increased activity in the white adipose tissue the specific activity of PAP1 in the liver of mice was that in adipose Consistent with the PAP1 activity lipin-1 protein levels in liver were also those in adipose tissue lipin-1 protein was detected in from the fld as shown in PAP1 activity in fld liver is with This the possibility that lipin-2 lipin-3 may for the of lipin-1 in fld this possibility, we lipin-2 and lipin-3 levels in and fld We that both genes are expressed in and that lipin-3 expression is increased in fld compared with mice These results that lipin-1 deficiency to of lipin-3 which may for the normal levels of PAP1 activity in the liver of fld this possibility, we lipin-2 and lipin-3 also possess PAP1 activity. and PAP1 of the Mg2+-dependent phosphatase in lipin-2 and lipin-3 suggested that these family members also have PAP1 activity. In the of two lipin-1 protein from and the of both lipin-1 exhibited PAP1 activity. The acid and not the phosphatase that both could PAP1 activity M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Recombinant lipin proteins were expressed in and PAP1 were by to the of lipin protein expressed as by the of a at the of recombinant protein We that both lipin-1 exhibited PAP1 activity However, the exhibited PAP1 activity to the and lipin-3 also PAP1 activity, at the specific activity of These results were under conditions PAP1 activity was to the of lipin to the and establish that all mammalian lipins have PAP1 activity. the of the PAP1 of the three lipin we a model of (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). the conditions the activity of PAP1 in the control was and all PAP1 activity was for by the lipin. The for the PAP1 of the lipins showed that the activity for was In this the for the PAP1 activity of lipin-2 was to that for with lipin-3 activity. Each lipin exhibited a for PA as demonstrated by the The for the lipins from to Each of the lipins showed and These results that all of the mammalian lipins possess PAP1 activity. However, the were with cell and we be that the reported those of Furthermore, the PAP1 of the lipins were as by this for the PAP1 activity of mammalian in a We also lysoPA, C1P, and as substrates for the different the conditions used to PA hydrolysis in the we Mg2+-dependent phosphatase activity with C1P, S1P, and lysoPA for of the lipins not and and Genes expression that the three lipin family members but tissue lipin-1 was in skeletal muscle, with levels in adipose tissue and liver These results from that lipin-1 is expressed at high levels in mouse adipose tissue and muscle (6Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar) and may a in In lipin-1 was in adipose tissue by skeletal muscle, with expression detected in of the and human lipin-2 were expressed at levels in liver and with human lipin-2 also high expression in adipose tissue and showed a distinct with expression in and other of the and Thus, the tissue in mouse and human are from the high expression of lipin-2 detected in but not mouse, adipose The basis for this may be a it may a of the human adipose tissue that was This from unknown and adipose tissue also be that different were used for the different the expression for can be compared for lipin but not the these results that of the lipin family members may perform biochemical but may in a Our results demonstrate for the first that all three members of the mammalian lipin protein family PAP1 activity. The lipin were specific for PA, and Mg2+. The lipins PA which the results of Han et al. (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar) for yeast PAP1 activity. phosphatase activity was detected under the conditions used for the mammalian lipins lysoPA, C1P, and Our results demonstrate that the mammalian lipins are distinct Mg2+-dependent PA the (14Brindley D.N. J. Cell. Biochem. 2004; 92: 900-912Crossref PubMed Scopus (186) Google Scholar, D.W. Gómez-Muñoz A. J. Brindley D.N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google do not have activity other lipid These results are with on yeast which is to DAG pyrophosphate (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). Our results that lipin-1, and distinct tissue expression patterns. The of PAP1 activity in from fld mice lipin-1 as the PAP1 in adipose tissue and skeletal muscle. These results are consistent with a by et al. A. J. A. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) that was this was in They demonstrated that and skeletal muscle from fld mice PAP1 activity A. J. A. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google but not PAP1 activity in adipose Our results demonstrate that lipin-1 is the PAP1 in both white and brown adipose tissue, the impaired TAG and lipodystrophy in the fld mutant mouse. The PAP1 activity of lipin-1 also the in adipocyte and TAG in transgenic mice with enhanced lipin-1 expression in adipose tissue (8Phan J. Reue K. Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 9Peterfy M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Lipin-1 expression was also detected at high levels in human adipose tissue, in with and we have Reue K. Phan J. M. J. A. J. A. K. P. Genet. 2006; PubMed Scopus Google Scholar, A. B. Phan J. Reue K. 2006; PubMed Scopus Google Scholar, M. J. J. Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). We have recently demonstrated that human adipose tissue lipin-1 levels in the human and that lipin-1 expression and mass and insulin Reue K. Phan J. M. J. A. J. A. K. P. Genet. 2006; PubMed Scopus Google Scholar, A. B. Phan J. Reue K. 2006; PubMed Scopus Google Scholar). the high levels of lipin-2 in the adipose tissue we is of the The role of lipin-1 as the muscle PAP1 is to the altered fat metabolism and energy expenditure in fld mice and muscle-specific lipin-1 transgenic mice (8Phan J. Reue K. Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). The to TAG in fld skeletal muscle may to to fatty acid to the in muscle fatty acid oxidation and reduced in fld increased lipin-1 expression in transgenic muscle results in increased TAG reduced fatty acid and energy expenditure (8Phan J. Reue K. Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). In addition to TAG synthesis, PAP1 activity is for the of and The fact that and develop in the fld mice a of PAP1 activity, the as to DAG is formed from PA to to Our results establish that adipose tissue and skeletal muscle have normal levels of activity, which also DAG from PA. However, and PAP1 The of the are to the of the membrane or the of (14Brindley D.N. J. Cell. Biochem. 2004; 92: 900-912Crossref PubMed Scopus (186) Google Scholar). By contrast, PAP1 activity is in the and it with the of the the major of glycerolipid P. Brindley D.N. PubMed Scopus Google Scholar). the to for PAP1 in synthesis, PA de novo have to the of the and the DAG formed to to the of glycerolipid synthesis. We that the and both PAP1 activity in a The that has specific activity suggests that the that are to the may or it is unknown in the of a cell also as a PAP1 is for the of in the This is the for which the of for the of DAG to Biochem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that lipin in the of yeast as a by PA Han G.S. Carman G.M. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). In lipin-1 to and the activity of the and the in of a of genes in liver Z. Cell Metab. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). to be a role for lipin-1 in other as adipose tissue, and the genes lipin-1 has been shown to gene expression adipocyte K. Donkor J. Future Lipidol. 2006; 1: 91-101Crossref Google Scholar, 9Peterfy M. Phan J. Reue K. J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). The PAP1 activity and expression of lipin-2 and lipin-3 that these lipin family members PAP1 in as and all three lipins are expressed to in the including and This lipin activity may have a role in the of membrane for the of the Furthermore, the glycerol phosphate pathway and PAP1 activity are for the and of fatty by of the of TAG is to glycerol D.N. Press, and Scholar). In the glycerol phosphate pathway is for the of of because the of is the major to TAG synthesis. The expression of the lipins in compared with and is with a role in fat However, the physiological of lipin expression in to be is that lipin-1-deficient fld mice not to have defect in or fat Phan and K. because of the of the other two lipin family members in this The identification of lipin family members as mammalian PAP1 enzymes to of the regulation of glycerolipid has been for that PAP1 activity is in adipose tissue in and diabetes Phosphatidate Phosphohydrolase: Its Role in Glycerolipid Synthesis. CRC Press, Inc., Boca Raton, FL1988: whereas the activity in liver in these conditions (12Brindley D.N. Phosphatidate Phosphohydrolase: Its Role in Glycerolipid Synthesis. CRC Press, Inc., Boca Raton, FL1988: 21-77Google but the for this regulation is not PAP1 is in the but is to to the as fatty acid and PA A. Brindley D.N. PubMed Scopus Google Scholar). Lipin-1 is in to insulin and A. J. A. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, A. PubMed Scopus Google that different levels of PAP1 and activity as suggested previously P. Brindley D.N. PubMed Scopus Google Scholar, Biochem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). on the yeast lipin homolog have recently identified that both PAP1 activity and of lipin to key enzymes in biosynthesis Han G.S. Carman G.M. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). in that the activity of mammalian lipins are at including gene protein and protein P. and B. be important to the of of these on PAP1 activity. In results and those of Han et al. (16Han G.S. Wu W.I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar) demonstrated that the yeast lipin ortholog exhibits PAP1 activity. The of lipin-1 in white and brown adipose tissue and skeletal muscle of the fld mouse results in a of PAP1 activity in these tissues. The liver PAP1 activity is in fld through expression of lipin-2 and which we also demonstrated to PAP1 activity. This of PAP1 activity is with the fatty liver and in the fld mouse the Z. Cell Metab. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). Lipin-1 not to catalyze in glycerolipid synthesis, but it also as a Our the for the expression of different lipins and this family of enzymes glycerolipid synthesis, cell and cell We for with with

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