A Conserved Serine Residue Is Required for the Phosphatidate Phosphatase Activity but Not the Transcriptional Coactivator Functions of Lipin-1 and Lipin-2

Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients. Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients. The mammalian lipin protein family is composed of three members, lipin-1, lipin-2, and lipin-3, each of which are ∼100 kDa in size and have 44–48% amino acid similarity (reviewed in Ref. 1Reue K. Brindley D.N. J. Lipid Res. 2008; 49: 2493-2503Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). Orthologous lipin genes are present in plants, invertebrates, and single cell eukaryotes such as yeast and plasmodium (2Péterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar), suggesting that lipin proteins play a fundamental cellular role that has been conserved in evolution. In particular, extended stretches of 100–200 amino acids at the N-terminal and C-terminal regions of the protein (the N-LIP and C-LIP domains, respectively) are highly conserved among the three mammalian lipin family members and among species. Within the C-LIP domain are two key protein functional motifs as follows: a haloacid dehalogenase motif (DXDXT) found in a superfamily of Mg2+-dependent phosphatases (3Han 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, 4Carman G.M. Han G.S. J. Biol. Chem. 2009; 284: 2593-2597Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar), and a transcription factor-binding motif (LXXIL) (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). These motifs confer two distinct molecular functions on members of the lipin family. All three mammalian lipins are Mg2+-dependent phosphatidate phosphatase (PAP) 4The abbreviations used are: PAPMg2+-dependent phosphatidate phosphatasePAphosphatidatePPARαperoxisome proliferator-activated receptor-αPGC-1αPPARγ coactivator protein-1αPPREPPAR-response elementqPCRquantitative PCRHADhaloacid dehalogenasefforwardrreverse. enzymes, which catalyze the conversion of phosphatidate (PA) to diacylglycerol, a key step in the biosynthesis of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine (3Han 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, 4Carman G.M. Han G.S. J. Biol. Chem. 2009; 284: 2593-2597Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 7Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Lipin-1 also acts as a transcriptional coactivator in hepatocytes, where it interacts with a complex containing peroxisome proliferator-activated receptor (PPAR) α and PPARγ coactivator-1α (PGC-1α) to regulate the expression of genes involved in fatty acid oxidation (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). Roles for lipin-2 and lipin-3 as transcriptional coactivators have not been characterized. Mg2+-dependent phosphatidate phosphatase phosphatidate peroxisome proliferator-activated receptor-α PPARγ coactivator protein-1α PPAR-response element quantitative PCR haloacid dehalogenase forward reverse. All three mammalian lipin family members function as PAP enzymes, raising the question of why multiple proteins are required. Previous gene expression studies in a panel of mouse and human tissues indicate that the three lipin genes have distinct but overlapping tissue distributions (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). Lipin-1 is most prominently expressed in adipose tissue, skeletal muscle, cardiac muscle, and testis, with lower expression in other tissues, including liver, kidney, and brain. Lipin-2 is expressed at high levels in liver and also to some extent in kidney, brain, and gut. Lipin-3 is expressed at much lower levels in the tissues surveyed, but mRNA is detectable in liver and gut. There is some overlap in the tissue expression of some lipin family members, making it unclear how each contributes to PAP and coactivator function. For example, lipin-1 and lipin-2 are both expressed in liver, although the relative levels and cell types in which they are expressed have not been definitively determined. Studies of PAP and coactivator activity in liver have thus far focused largely on lipin-1, which is required for normal induction of fasting-induced gene expression (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar), and accounts for the glucocorticoid-regulated PAP activity in this tissue (8Manmontri B. Sariahmetoglu M. Donkor J. Bou Khalil M. Sundaram M. Yao Z. Reue K. Lehner R. Brindley D.N. J. Lipid Res. 2008; 49: 1056-1067Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). has also lipin-2 as to PAP which is in the liver of is by and is in M.C. Harris T.E. Han Chen Z. B.N. J. Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar). In studies of lipin-1 or lipin-2 in cells and cells indicate that lipin-1 and lipin-2 have distinct functions Han G.S. Carman G.M. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). that lipin-1 and lipin-2 play distinct from in and The of the lipin lipin-1, is the gene in the fatty liver mouse (2Péterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar), which a mutation of mouse and to M.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. Xu P. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). with tissue lipin-1 contributes the of PAP activity in adipose tissue and (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 7Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Lipin-1 is also expressed in where it is required for normal cell function K. Han G.S. Carman G.M. R. 2008; PubMed Scopus Google Scholar), and in liver, where it a role in to and in (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, B. Sariahmetoglu M. Donkor J. Bou Khalil M. Sundaram M. Yao Z. Reue K. Lehner R. Brindley D.N. J. Lipid Res. 2008; 49: 1056-1067Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, Khalil M. Sundaram M. B. Sariahmetoglu M. K. Reue K. Brindley D.N. Yao Z. J. Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. Gropler M.C. J. Lawrence Jr., J.C. Harris T.E. B.N. Biol. 2008; PubMed Scopus Google Scholar). in human have been detected and recurrent in A. A. P. A. J. Genet. 2008; Full Text Full Text PDF PubMed Scopus (170) Google Scholar), a role for lipin-1 in human function. on phenotypes from human and mouse lipin-1 has a function in is the of lipin-2 or lipin-3 mouse for family members have not been characterized. human in the LPIN2 gene Majeed syndrome, inflammatory disorder characterized by recurrent osteomyelitis, dyserythropoietic anemia, and cutaneous inflammation Res. 2007; PubMed Scopus Google Scholar, 2007; PubMed Scopus Google Scholar). These symptoms indicate that lipin-2 a function in distinct LPIN2 have been in In of two in the lipin-2 to a in the of the protein Chen A. A. Majeed J. Genet. PubMed Scopus Google Scholar), in mRNA and functional protein mutation in the site for of the LPIN2 which to of amino acid a R. 2007; PubMed Scopus Google Scholar). both of of lipin-2 the mutation is a mutation that to a single amino acid S734L Chen A. A. Majeed J. Genet. PubMed Scopus Google Scholar). The affected serine in the C-LIP domain of the PAP site and transcriptional coactivator serine is conserved in three lipin family members and most suggesting a that is required for activity a transcriptional coactivator function. Here we characterize the of mutating the conserved serine on the PAP and coactivator functions of lipin-1 and the Majeed syndrome and this the question of lipin-2 has a role in the functions of To we a expression of lipin-2 by in situ hybridization of whole and of tissues relevant to Majeed syndrome. were from the All were mouse and were on a studies were of the and of and lipin-1 and lipin-2 expression were as (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). was the used are as follows: and and and and and and cells were in with and and at in were with the cells were and for PAP or activity. PAP were as (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). cells were in containing PAP phosphatase and and We PAP activity in a of containing and with in and Z. A. A. Brindley D.N. J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. A. Z. Brindley D.N. PubMed Scopus Google Scholar). The of in the was to were at with of containing as for of was to the and by A. A. Z. Brindley D.N. PubMed Scopus Google Scholar). The were and of the which the was and by by the and the of were that of the was the PAP were from at three protein to the of the The in containing to the of phosphatase activity to the activity. activity was with that of the PAP and was in PAP activity was to lipin protein expression by quantitative of protein from each were in and to a were with in and with mouse to were detected was detected with the and with cells were with a with by and or lipin expression a to demonstrate of the the was with a in which the were cells were in and in and were the activity was to activity to for in In each were in of the of and lipin-2 proteins to to was our R. P. A. J. Brindley D.N. J. PubMed Scopus Google Scholar). of were with of and in containing and to with The were at for for and the was for a for to the microsomal was at in containing fatty and for to fatty acids and lipin from the The microsomal were at as and in the lipins were expressed in which were in containing and and to with and phosphatase and from The was for for to lipin-2 to and in the For the of liver microsomal protein was for at in a of of containing and The from the cells containing lipin of was and the were for at to the lipins and R. P. A. J. Brindley D.N. J. PubMed Scopus Google Scholar). the were on for The proteins were at for at The were in of The were with of at The protein was by and in of for were with from and at was from mouse liver with and was from of The was by of lipin-2 and lipin-1 the and by of with or were by in To for and we a of mouse lipin-2 and and it were to for and and by with In situ hybridization was the of of was by in transcription and to mouse whole or tissue sections were from for in the tissues were from with and as were on and at were at in yeast and The tissues were to at in and in with at for in and for at the were to for and in and in with at for was in were with and both and to the levels of hybridization and tissues were from blood cells were from whole blood at for at The was two and the blood cell was from by of erythrocytes of at for and cells in by at for were in containing and the was used for and were from blood cells or tissues and as was with as (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, J. Reue K. J. Metab. 2008; PubMed Scopus Google Scholar). were as follows: lipin-1, lipin-2, and lipin-3, were with as in the the and were for The Majeed S734L mutation in human lipin-2 a serine that is in the C-LIP domain of the site and coactivator motifs The affected serine is conserved in lipin-1, and in and in proteins in other species. We the for the Majeed syndrome in S734L mutation in lipin-2 by PAP activity of mouse lipin-2 with a leucine at the serine We also the mutation in mouse at Lipin-1 protein in two and that result from mRNA both of which have PAP activity (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). The was in studies We expressed and in cells and determined PAP activity in cell and lipin-2 as and lipin-2 PAP activity and respectively) mutation of the PAP motif or the coactivator motif PAP as has been (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). The serine to leucine found in Majeed PAP activity in both lipin-1 and lipin-2 lipin-2 and proteins were expressed at similar that the of PAP activity is not to protein levels or protein and not of the to acid PAP activity in both and lipin-2, that activity by the of a Studies to the molecular of the lipin that PAP in the of the to to catalyze the PAP reaction cells are with than fatty acids R. P. A. J. Brindley D.N. J. PubMed Scopus Google Scholar, A. G.M. A. Z. Brindley D.N. PubMed Scopus Google Scholar). lipin-2 is to largely with the expressed in cells Han G.S. Carman G.M. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), fatty has been for Therefore, we lipin-2 and association is by mutation of the Majeed serine and from cells similar levels of lipin-2 or were used for than as not to of lipin-2 that to These of lipin-2 were to liver which been of lipins by with in the of and lipin-2 to and The relative of lipin-2 in the and that were were determined by and lipin-2 levels were to levels of and which not in the of lipin-2 was present at similar levels in and in the of and it to the with levels of and in association and in multiple a with lipin-2, in the of was in and lipin-2 the protein normal suggesting that the amino acid at this is not a of as as the and of lipin-2 two The lipin-2 of the the a high of the result is with that for lipin-1 where a with T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, Han G.S. Carman G.M. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the of lipin-2 in the Majeed syndrome to a of the protein to with that the lipin-2 protein in that Lipin-1 functions as a coactivator in the to transcriptional of genes in (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). the motif present in the C-LIP domain of lipin-1 is conserved in lipin-2, we the of lipin-2 to transcription a were a gene in were with the and PPARγ and receptor-α expression in the and of and or lipin expression to results for (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar), expression for to and the of the coactivator activity of with that of required a functional as of this element Lipin-2 coactivator activity as lipin-1, of the on lipin-2 with and of the of α lipin-2 with the coactivator activity to and the serine that is required for PAP activity of both lipin-1 and lipin-2 is not required for coactivator function. We that the three lipin genes have but expression a panel of mouse and human tissues (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar). To a of lipin-2 tissue expression the including tissues that are affected in Majeed syndrome such as and we used in situ hybridization with lipin-2 on whole mouse was observed at high levels in the liver, as as in specific regions of the gastrointestinal tract, kidney, and a hybridization was with lipin-2 and in and In the liver, lipin-2 a with observed are as in for by and has been that lipin-1 is expressed in liver, where it is also by (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). we determined that lipin-1 by and lipin-2 by it has been unclear lipin-1 or lipin-2 is expressed at higher levels in the To we to lipin-1 and lipin-2 with the and to the by The PCR a from both lipin-1 and lipin-2 of the with the lipin-2 and but not In with the lipin-1 to and but not lipin-2 that lipin-2 mRNA levels in liver are higher than lipin-1 suggesting that lipin-2 may contribute to PAP activity and coactivator activity in this expression in the cell in tissues of the and In situ hybridization was on mouse tissues to lipin-2 mRNA or as a of sections are in the Lipin-2 mRNA was detected in the the in the cell and cells of the and in of the Lipin-2 mRNA was not detected in the of the In to liver, in situ hybridization levels of lipin-2 expression in the gastrointestinal was detected in of the and the the cell of the and in cell of the and Lipin-2 expression in was detected in the and not In brain, lipin-2 was expressed in the and and results not Lipin-2 was also expressed in the and as as the and we not lipin-2 expression in situ hybridization in or tissues that in Majeed syndrome Res. 2007; PubMed Scopus Google Scholar, 2007; PubMed Scopus Google Scholar). The of lipin-2 expression in was the of in lipin-1 mRNA detected at levels in We detected levels of lipin-2 expression in and marrow, at the levels in liver We also the anemia and inflammatory observed in Majeed syndrome may a role for lipin-2 in red blood cells and we detected mouse lipin-2 expression in circulating red blood in whole and the blood cell of and in thymus, at of the levels observed in liver, where lipin-2 is expressed at levels of gene expression among three lipin genes are not PCR on the that lipin-2 is expressed at much higher levels in liver than lipin-1 or lipin-3 (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar), lipin-2 to the lipin mRNA expressed in red blood cells and tissues was to the functional of the serine that is in the Majeed syndrome and that is conserved in lipin proteins from species. The S734L mutation the C-LIP domain that is conserved among lipin family members but is distinct from the and transcriptional coactivator protein of the serine to leucine or aspartate abolishes the PAP activity of lipin-1 and the lipin-2 protein was to with membranes, a key step in the expression of PAP activity. We also the that lipin-2 transcriptional coactivator activity equivalent to coactivator function is the Majeed serine is results the conserved serine as for the function of lipins as enzymes, and that a in Majeed syndrome is the loss of lipin-2 PAP activity. is that lipin protein in including and plants, have serine at the affected by the Majeed most have a that the of a at this is for the of the lipins with to phosphatase activity. is with the of the haloacid dehalogenase superfamily of proteins J. Biol. 2006; PubMed Scopus Google to which the lipins The proteins conserved motifs that are for domain activity as follows: a by the a by a conserved which is involved in the to in the site of the proteins J. Biol. 2006; PubMed Scopus Google and and two motif The the sites of lipin-1 and lipin-2 are to the as characterized protein family members The serine in the motif is we that and were of PAP activity. Therefore, we that the of serine or in this is also for the of the site of lipin family for this the of a lipin protein the studies also that lipin-2 function as a transcriptional coactivator for as for lipin-1 (5Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar). The serine to leucine in Majeed syndrome not lipin-2 coactivator that the of this serine for the of the site does not the of the we that symptoms observed in with the S734L Majeed mutation to a of lipin-2 coactivator activity. Majeed with a loss of both lipin-2 PAP and coactivator function. is to that have symptoms than with the serine with fever, and dyserythropoietic anemia, with the mutation and anemia and required blood Chen A. A. Majeed J. Genet. PubMed Scopus Google Scholar). is that loss of both lipin-2 PAP and coactivator is than the loss of PAP of the of it is not to or as of has not been to the by which lipin-2 mutation results in the symptoms observed in Majeed syndrome of the of human and the of such studies in we a of tissues and cell types in which lipin-2 is expressed in the mouse to function in normal and the of loss of function in Majeed syndrome. In with our quantitative PCR results on a panel of tissues (6Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar), the liver the lipin-2 a we determined that lipin-2 mRNA levels are higher than of lipin-1 with role for lipin-2 PAP activity in the liver M.C. Harris T.E. Han Chen Z. B.N. J. Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar). we lipin-2 expression the hepatocytes, that it is not to cell such as or The in situ hybridization studies also of lipin-2 in and other and and of the gastrointestinal cell in regions from to the We also detected lipin-2 expression in circulating red blood cells and tissues, including thymus, and Lipin-2 PAP in tissues contribute to the anemia and inflammation with Majeed syndrome. The by which lipin-2 PAP are but are by studies of lipin-1 in and of lipin-2 PAP activity may to cells that on this protein for of phosphatidylcholine, and triacylglycerol, the key that on by are for example, in which are and of to and in adipose tissue K. Xu P. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar, J. Reue K. Cell Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). of lipin-2 PAP is the of such as which acts as a the cell PubMed Scopus Google Scholar, R. Lipid Res. 2006; PubMed Scopus Google Scholar, A. 2009; 49: PubMed Scopus Google Scholar, D.N. Sariahmetoglu M. Reue K. 2009; PubMed Scopus Google Scholar). of in cells to the protein to which contributes to the in K. Han G.S. Carman G.M. R. 2008; PubMed Scopus Google Scholar). in skeletal as a result of mutation of the gene in human is with A. A. P. A. J. Genet. 2008; Full Text Full Text PDF PubMed Scopus (170) Google Scholar). studies in a mouse on the role of lipin-2 in glycerolipid cell by and and in the that we in this also the of lipin-2 in the of Majeed syndrome. We Xu for

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