Lipin 2 Is a Liver-enriched Phosphatidate Phosphohydrolase Enzyme That Is Dynamically Regulated by Fasting and Obesity in Mice

Abstract

Lipin 1 is a bifunctional intracellular protein that regulates fatty acid metabolism in the nucleus via interactions with DNA-bound transcription factors and at the endoplasmic reticulum as a phosphatidic acid phosphohydrolase enzyme (PAP-1) to catalyze the penultimate step in triglyceride synthesis. However, livers of 8-day-old mice lacking lipin 1 (fld mice) exhibited normal PAP-1 activity and a 20-fold increase in triglyceride levels. We sought to further analyze the hepatic lipid profile of these mice by electrospray ionization mass spectrometry. Surprisingly, hepatic content of phosphatidate, the substrate of PAP-1 enzymes, was markedly diminished in fld mice. Similarly, other phospholipids derived from phosphatidate, phosphatidylglycerol and cardiolipin, were also depleted. Another member of the lipin family (lipin 2) is enriched in liver, and hepatic lipin 2 protein content was markedly increased by lipin 1 deficiency, food deprivation, and obesity, often independent of changes in steady-state mRNA levels. Importantly, RNAi against lipin 2 markedly reduced PAP-1 activity in hepatocytes from both wild type and fld mice and suppressed triglyceride synthesis under conditions of high fatty acid availability. Collectively, these data suggest that lipin 2 plays an important role as a hepatic PAP-1 enzyme. Lipin 1 is a bifunctional intracellular protein that regulates fatty acid metabolism in the nucleus via interactions with DNA-bound transcription factors and at the endoplasmic reticulum as a phosphatidic acid phosphohydrolase enzyme (PAP-1) to catalyze the penultimate step in triglyceride synthesis. However, livers of 8-day-old mice lacking lipin 1 (fld mice) exhibited normal PAP-1 activity and a 20-fold increase in triglyceride levels. We sought to further analyze the hepatic lipid profile of these mice by electrospray ionization mass spectrometry. Surprisingly, hepatic content of phosphatidate, the substrate of PAP-1 enzymes, was markedly diminished in fld mice. Similarly, other phospholipids derived from phosphatidate, phosphatidylglycerol and cardiolipin, were also depleted. Another member of the lipin family (lipin 2) is enriched in liver, and hepatic lipin 2 protein content was markedly increased by lipin 1 deficiency, food deprivation, and obesity, often independent of changes in steady-state mRNA levels. Importantly, RNAi against lipin 2 markedly reduced PAP-1 activity in hepatocytes from both wild type and fld mice and suppressed triglyceride synthesis under conditions of high fatty acid availability. Collectively, these data suggest that lipin 2 plays an important role as a hepatic PAP-1 enzyme. Spontaneously arising mutations in the gene encoding lipin 1 (Lpin1) cause severe metabolic abnormalities in fatty liver dystrophic (fld) mice (1Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar), which exhibit neonatal growth retardation, fatty liver, and dyslipidemia (2Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar). These phenotypic manifestations abruptly resolve at ∼14 days of age. However, adult fld mice exhibit lipodystrophy, insulin resistance, and susceptibility to atherosclerotic lesion formation (3Rehnmark S. Giometti C.S. Slavin B.G. Doolittle M.H. Reue K. J. Lipid Res. 1998; 39: 2209-2217Abstract Full Text Full Text PDF PubMed Google Scholar, 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). Recent evidence regarding the molecular functions of lipin 1 has begun to explain the severe metabolic phenotype of these mice. Lipin 1 catalyzes the Mg2+-dependent dephosphorylation of phosphatidic acid (phosphatidic acid (PA) 2The abbreviations used are: PAP-1, phosphatidic acid (PA) phosphohydrolase; PGC-1α, peroxisome proliferator-activated receptor α coactivator 1α; ADRP, adipophilin; P-, post-natal day; ESI-MS, electrospray ionization mass spectrometry; DG, diacylglycerol; TG, triglyceride; WT, wild type; DMEM, Dulbecco’s modified Eagle’s medium; HA, hemagglutinin; shRNA, short hairpin RNA; siRNA, small interfering RNA; PG, phosphatidylglycerol; CL, cardiolipin; PI, phosphatidylinositol. phosphohydrolase (PAP-1) (5Han 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)) to form diacylglycerol (DG), the penultimate step in the Kennedy pathway of triglyceride (TG) synthesis (Fig. 1A). As proof of the importance of lipin 1-mediated PAP-1 activity, fld mice almost completely lack this enzymatic activity in adipose tissue, skeletal muscle, and heart (6Harris 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), and the inability to synthesize TG in adipocytes may explain the defect in adipogenesis in fld mice. Interestingly, lipin 1 is a soluble protein, and significant lipin 1 localization to the nucleus has also been demonstrated (1Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar). Moreover, recent evidence suggests that lipin 1 functions as a regulator of gene transcription via protein-protein interactions with DNA-bound transcription factors (7Finck 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, 8Santos-Rosa H. Leung J. Grimsey N. Peak-Chew S. Siniossoglou S. EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (293) Google Scholar), including the peroxisome proliferator-activated receptor α (PPARα) and its coactivator protein PPARγ-coactivator 1α (PGC-1α) (7Finck 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). PAP-1 catalytic activity is not required for peroxisome proliferator-activated receptor α coactivation, and these two molecular functions seem to be completely separable. Thus, lipin 1 is poised to play important roles in controlling the metabolism of fatty acids at multiple regulatory levels. Given the role of lipin 1 as an enzyme in TG synthesis, the hepatic phenotype of fld mice is somewhat surprising. First, neonatal fld mice exhibit severe hepatic steatosis because of over-accumulation of TG (2Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar). Second, although other tissues of fld mice are severely deficient in PAP-1 activity, the liver of adult fld mice retains significant Mg2+-dependent PAP activity (6Harris 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, 9Donkor 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) and normal rates of TG synthesis (10Chen Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (69) Google Scholar). These findings suggest that other PAP-1 enzymes are active in liver. Based on sequence homology in signature N- and C-terminal domains, two additional lipin family proteins (lipin 2 and lipin 3) been (1Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar). Importantly, lipin 2 and exhibit PAP-1 activity, although the activity and (lipin 1 lipin 2 lipin 3) 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 further the hepatic phenotype of fld mice by mass of and the and of the PAP-1 protein, lipin of mice were used to and mice. was from and with mice been T.C. Finck B.N. S. M. D.F. N. Chen Z. Kelly D.P. Biol. 2005; PubMed Scopus Google Scholar). were with mice which were food for at food at and to for were by the of of Cell were in DMEM, hepatocytes were from mice as Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). were by hepatocytes with in a at an of of were in lipin 2 TG synthesis rates were by as (7Finck 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, Z. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). lipin 2 was the and the lipin 2 was to of the and was the and the to was as a has been (7Finck 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 was used to synthesize for lipin 2 and a sequence sequence for the lipin 2 are and were hepatocytes Based on of was for metabolic was the hepatocytes were for in and a of of was were Lipid of TG and been 2001; PubMed Scopus (299) Google Scholar, J. H. H. PubMed Scopus Google Scholar). were from liver a modified and in the of for electrospray ionization mass were a mass with an PAP-1 acid (PAP-1) activity was by a of the of Carman and G.M. PubMed Scopus Google Scholar) to from acid phosphatidic acid was by and diacylglycerol to of were to a of 2 acid and at the were by of in was by 1 of and 1 of 1 of soluble in of the was by Mg2+-dependent PAP activity (PAP-1) was by activity in the of from activity in the of of activity was under conditions for at in a of as N. B.G. PubMed Scopus Google Scholar). of liver and was the as a which was by with in at a of in a by under a of and in was by liver proteins to the and by of a were from this and on with acid to TG was from the and for a in which liver proteins were were used as for and were for lipin 2 and lipin were from the 2 by and with enzyme. were by were for 2 at were and to were against the lipin 2 lipin (6Harris 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 liver fatty protein of for lipin 2 and were by by with the (lipin 2) Lipin 2 and were the was the sequence and the of mRNA were by the of sequence of the used in be in hepatocytes from adult and fld mice were were with to lipin 2 and in for this the hepatocytes were with and in and for 1 the was with 1 of and of for 2 was for this the hepatocytes were in 1 of and for the the were in an and a of lipin 2 and proteins in the were and by as for the of proteins (10Chen Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (69) Google Scholar). by adult mice were and for liver from both mice was with a and livers were to a with 2 of 1 and with at was for at the was in was a was for at in a was with a were and proteins were by of was that the of protein as is in were of data are as the with a significant as a of fld TG and the important role that lipin 1 plays in TG synthesis, livers of neonatal fld mice a of lipid and high of and TG (2Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar, K. Doolittle M.H. J. Lipid Res. Full Text PDF PubMed Google Scholar). has also demonstrated that hepatic PAP-1 activity is 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) (6Harris 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) in adult fld mice. However, PAP-1 activity in fld livers has not been We that PAP-1 activity to be increased in post-natal fld liver with (Fig. that this pathway is and that lipin 1 is not required for PAP-1 activity was also in fld liver. We sought to analyze of hepatic lipid of lipin 1 in the Kennedy pathway by These that TG content was increased 20-fold in fld liver at with mice (Fig. increase in TG content in fld mice was TG content of other phospholipids derived from of PAP-1 and (Fig. and data not were We of lipid of lipin 1 in the TG synthesis Surprisingly, the hepatic content of the PAP-1 substrate phosphatidic acid (PA) was markedly in lipin livers (Fig. were also diminished in fld liver (Fig. was to of the and (Fig. and which is derived from PG, was also in fld liver (Fig. PAP-1 activity is not required for the of to CL, and of these phospholipids is by diminished of were of and fld of mice. Lipin 2 a Lipin the of PAP-1 activity in fld liver, sought to the and of other lipin family of is the of mRNA was in liver by (Fig. against against lipin 2 a in liver (Fig. that with lipin 2 protein via an not tissues that were were of lipin 2 Lipin 1 is a soluble protein that also be to the nucleus with endoplasmic reticulum (1Peterfy M. Phan J. Xu P. Reue K. Nat. Genet. 2001; 27: 121-124Crossref PubMed Scopus (475) Google Scholar, 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, N. G.S. Carman G.M. Siniossoglou S. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the localization of lipin 2 in liver, hepatic were by A. Croce M.A. Gropler M.C. A. N. Finck B.N. 2006; PubMed Scopus Google Scholar). the of lipin 2 in the liver, the were by that the protein in the in Lipin 2 localization was by with of the including the lipid soluble fatty endoplasmic reticulum and of lipin 2 were in lipid endoplasmic reticulum and (Fig. However, the of lipin 2 was in the soluble (Fig. soluble also the of lipin 2 protein of protein were in (Fig. to lipin 1 (6Harris 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, T.A. Lawrence Jr., J.C. S. A. PubMed Scopus Google Scholar), the lipin 2 often as a because of N. G.S. Carman G.M. Siniossoglou S. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). of lipin 1 is a of (6Harris 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), and the sequence this is with lipin 2 We that an against of lipin 1 also lipin 2 lipin the of lipin 2 was in the soluble of the liver (Fig. the of the lipin 2 was in the soluble of the was for of the of protein (Fig. suggests that under these the of lipin 2 protein is in the the lipin 1 (6Harris 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 2 in to Lipin 2 in fld via a with 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, Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (69) Google Scholar), mRNA was not in liver of fld mice with (Fig. However, lipin 2 protein content was increased in fld mice of (Fig. Moreover, at of a in a significant increase in lipin 2 protein mRNA levels. increase in lipin 2 protein in hepatocytes from fld mice is also days in not These data suggest that lipin 2 protein content is increased in fld liver independent of changes in steady-state mRNA levels. sought to lipin 2 synthesis rates and in metabolic with As in the of of lipin 2 was in hepatocytes from and fld mice. However, the of lipin 2 synthesis in metabolic in was increased in fld that the mRNA and protein is to increased rates of Lipin 2 in a of hepatic of is increased by of (7Finck 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). Similarly, both lipin 2 mRNA and protein were by food (Fig. that lipin 2 are also under in lipin 1 from the that the increase in required an pathway in liver (7Finck 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). However, hepatic was in and mice (Fig. Moreover, although is by in mRNA and lipin 2 protein were not (Fig. Thus, the regulatory that hepatic and are Lipin 2 an PAP-1 in the of lipin 2 on PAP-1 activity, hepatocytes were with an to lipin Lipin 2 PAP-1 activity TG synthesis rates in hepatocytes (Fig. which lipin were with lipin 2 PAP-1 activity was increased (Fig. However, this was also not to an increase in TG synthesis as as a (Fig. to the metabolic of lipin 2 in the high of lipin 2 and the of PAP-1 activity seem to the of a in this an lipin 2 shRNA, which markedly reduced lipin 2 protein in hepatocytes (Fig. Interestingly, lipin 2 to a increase in mRNA in fld hepatocytes (Fig. However, lipin protein by and lipin 2 reduced PAP-1 activity in both and fld hepatocytes (Fig. a in PAP-1 activity, rates of TG synthesis were not by lipin 2 in (Fig. These findings suggest that PAP-1 activity is for normal TG synthesis in hepatocytes under Given these sought to the of lipin 2 in the of increased fatty acid which is a to TG synthesis. to regarding increased of hepatocytes to the of these Lipin 2 were hepatocytes from and fld mice. lipin 2 to a in lipin 2 protein and a in PAP-1 activity not rates of TG synthesis were by lipin 2 in fld hepatocytes (Fig. hepatocytes with acid for TG synthesis. As increased TG synthesis rates the in the and the of lipin 1 with lipin 2 suppressed TG synthesis rates (Fig. that PAP-1 activity We also the of lipin 2 in hepatocytes from fld which increased lipid and rates of TG synthesis (10Chen Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (69) Google Scholar). Lipin 2 to a significant of TG synthesis rates to in hepatocytes at and (Fig. Lipin 2 also to TG synthesis rates in hepatocytes of this age. of Lipin 2 a in TG in that lipin 2 TG synthesis rates in to increased fatty acid the role of lipin 2 in controlling TG synthesis in We that the of mRNA was not in and mice with (Fig. However, a increase in lipin 2 protein in both with (Fig. of lipin 2 as an important to lipin 2 from and mice were and with lipin 2 to the of lipin 2 on hepatic TG synthesis. Interestingly, lipin 2 suppressed rates of TG synthesis in hepatocytes to with (Fig. Moreover, the increase in TG synthesis in hepatocytes was markedly These data suggest that the increase in lipin 2 in mice to the for TG synthesis. Lipin 1 is the member of a family of Mg2+-dependent phosphohydrolase enzymes that catalyze the penultimate step in TG synthesis (5Han 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). PAP-1 activity is in adipose tissue, muscle, and heart of lipin fld mice (6Harris 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). However, liver of adult fld mice hepatic PAP-1 activity (6Harris 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, 9Donkor 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). that hepatic PAP-1 activity was not in liver of neonatal fld which hepatic TG is that the high of lipin 2 in liver and the lack of of other in and adipose may explain these lipin 2 is enriched in liver, which to be the of its Moreover, lipin 2 protein were increased in liver of both 8-day-old and adult fld mice with that lipin 2 is to for lipin 1 RNAi demonstrated that lipin 2 a in PAP-1 activity in both and fld and that lipin 2 is an important PAP-1 enzyme in These data recent findings lipin 2 in N. G.S. Carman G.M. Siniossoglou S. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). that lipin 2 to increased PAP-1 activity to a of lipin 1 mRNA and is for these the importance of lipin 1 and 2 as PAP-1 enzymes is lipin 2 data also suggest that lipin not play a significant role as a PAP-1 enzyme in liver. that is in fld liver and for lack of lipin 1 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). this mRNA was also by lipin 2 in fld However, the of lipin as mRNA and protein were by and lipin 2 with the activity of lipin 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), its role as a PAP-1 enzyme in liver is However, PAP-1 activity was not completely by lipin 1 with lipin 2 activity is to lipin 2 protein 2) the of lipin 3) the of other PAP-1 enzymes that not been lipin 2 was not to increase PAP-1 activity in activity of lipin proteins to be by (6Harris 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, N. G.S. Carman G.M. Siniossoglou S. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). is that these factors PAP-1 activity in However, in lipin 2 a increase in PAP-1 is that lipin hepatocytes an of this lipin 2 not TG synthesis in a increase in PAP-1 in PAP-1 activity not rates of TG synthesis under in fld activity to be for normal TG synthesis under these is that the step in this pathway is for TG synthesis J. 2007; PubMed Scopus Google Scholar), and data are with As by with adult fld mice increased lipin 2 not TG synthesis is that lipin 2 in fld mice is not the for hepatic fatty acid triglyceride synthesis and increased of lipid to the liver to high content is the with the and fatty liver of fld mice and resolve (2Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar). Lipin 2 plays a role by the for TG synthesis by high fatty acid availability. hepatocytes were with high of fatty the phenotype by of lipin 2 and demonstrated significant in rates of TG synthesis. is at the other of the phenotypic from lipodystrophy, also high lipid as as increased hepatic lipin findings suggest that lipin 2 is also in the increased rates of TG synthesis in hepatocytes as are to of lipin 2 in liver at hepatic fatty liver of fld mice is a metabolic signature of this has that the hepatic content of and TG is increased in these mice (2Langner C.A. Birkenmeier E.H. Ben-Zeev O. Schotz M.C. Sweet H.O. Davisson M.T. Gordon J.I. J. Biol. Chem. 1989; 264: 7994-8003Abstract Full Text PDF PubMed Google Scholar, K. Doolittle M.H. J. Lipid Res. Full Text PDF PubMed Google Scholar). We the hepatic lipid profile of these mice further by with the that the substrate of lipin phosphatidic in these was markedly in liver of fld mice. a recent that in the of fld mice K. G.S. S. Carman G.M. M.H. 2008; PubMed Scopus Google Scholar). Lipin 2 not seem to be in the and is that this the demonstrated that phosphatidylglycerol and cardiolipin, which are derived from were also in fld liver. is a of the M. 2005; Google Scholar), and abnormalities in synthesis and cause in M. M. 2006; PubMed Scopus Google Scholar, J. Cell 2007; PubMed Scopus Google Scholar). is to that to in fatty acid in hepatocytes from neonatal fld mice (3Rehnmark S. Giometti C.S. Slavin B.G. Doolittle M.H. Reue K. J. Lipid Res. 1998; 39: 2209-2217Abstract Full Text Full Text PDF PubMed Google Scholar) and hepatic steatosis in this We also that the regulatory that the of and are both are by food (Fig. and Sariahmetoglu M. J. M. Z. Reue K. Brindley D.N. J. Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar), the of required the of the coactivator (7Finck 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), with data that steady-state mRNA are not by Sariahmetoglu M. J. M. Z. Reue K. Brindley D.N. J. Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) Gropler and N. (Fig. which cause a increase in hepatic S. S. A. P. M. 2001; PubMed Scopus Google Scholar, J.C. P. Chen J. Wu Z. J. J. 2001; PubMed Scopus Google Scholar). that of the of lipin 1 by food was to and activity as a coactivator (7Finck 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). to be lipin 2 also in the nucleus as a regulatory protein and a of the to in the also that lipin 2 protein content was independent of changes in steady-state mRNA levels. fld lipin 2 protein were was of lipin 2 was not to fld as and mice also exhibit increased lipin 2 protein independent of changes in of metabolic that in steady-state lipin 2 protein are via increased rates of lipin 2 protein of lipin 2 is an important regulatory and of protein be for of of lipin 1 in a hepatic phenotype that is at in by a of the lipin family lipin that lipin 2 is an important hepatic PAP-1 enzyme that is under the of regulatory Given recent evidence that mutations in the gene encoding lipin 2 are to the of J. M. A. N. M. A. 2007; PubMed Scopus Google Scholar) and a Chen S. A. A. S. H. J. Genet. 2005; PubMed Scopus Google Scholar, 2007; PubMed Scopus Google Scholar), further be to the of metabolic by lipin 2 and to the molecular that lipin 2