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

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.

[1]  G. Carman,et al.  Temporal and Spatial Regulation of the Phosphatidate Phosphatases Lipin 1 and 2 , 2008, Journal of Biological Chemistry.

[2]  T. Harris,et al.  Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[3]  G. Carman,et al.  Phosphatidic acid mediates demyelination in Lpin1 mutant mice. , 2008, Genes & development.

[4]  A. Hofman,et al.  LPIN2 Is Associated With Type 2 Diabetes, Glucose Metabolism, and Body Composition , 2007, Diabetes.

[5]  P. Ferguson,et al.  A splice site mutation confirms the role of LPIN2 in Majeed syndrome. , 2007, Arthritis and rheumatism.

[6]  J. Shabanowitz,et al.  Insulin Controls Subcellular Localization and Multisite Phosphorylation of the Phosphatidic Acid Phosphatase, Lipin 1* , 2007, Journal of Biological Chemistry.

[7]  K. Reue,et al.  Three Mammalian Lipins Act as Phosphatidate Phosphatases with Distinct Tissue Expression Patterns* , 2006, Journal of Biological Chemistry.

[8]  N. Wolins,et al.  OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization , 2006, Diabetes.

[9]  M. Schlame,et al.  Barth syndrome, a human disorder of cardiolipin metabolism , 2006, FEBS letters.

[10]  T. Harris,et al.  Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway , 2006 .

[11]  G. Carman,et al.  The Saccharomyces cerevisiae Lipin Homolog Is a Mg2+-dependent Phosphatidate Phosphatase Enzyme*♦ , 2006, Journal of Biological Chemistry.

[12]  S. Leal,et al.  Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome) , 2005, Journal of Medical Genetics.

[13]  S. Siniossoglou,et al.  The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth , 2005, The EMBO journal.

[14]  Michael Courtois,et al.  PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis , 2005, PLoS Biology.

[15]  M. Zhang,et al.  Cardiolipin in energy transducing membranes , 2005, Biochemistry (Moscow).

[16]  Xianlin Han,et al.  Toward fingerprinting cellular lipidomes directly from biological samples by two-dimensional electrospray ionization mass spectrometry. , 2004, Analytical biochemistry.

[17]  J. Lawrence,et al.  Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Marc Montminy,et al.  CREB regulates hepatic gluconeogenesis through the coactivator PGC-1 , 2001, Nature.

[19]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[20]  Xianlin Han,et al.  Quantitative analysis and molecular species fingerprinting of triacylglyceride molecular species directly from lipid extracts of biological samples by electrospray ionization tandem mass spectrometry. , 2001, Analytical biochemistry.

[21]  Ping Xu,et al.  Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin , 2001, Nature Genetics.

[22]  G. Schonfeld,et al.  A Targeted Apolipoprotein B-38.9-producing Mutation Causes Fatty Livers in Mice Due to the Reduced Ability of Apolipoprotein B-38.9 to Transport Triglycerides* , 2000, The Journal of Biological Chemistry.

[23]  P. Xu,et al.  Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. , 2000, Journal of lipid research.

[24]  K. Reue,et al.  The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. , 1998, Journal of lipid research.

[25]  K. Reue,et al.  Naturally occurring mutations in mice affecting lipid transport and metabolism. , 1996, Journal of lipid research.

[26]  R. Coleman,et al.  Increased hepatic monoacylglycerol acyltransferase activity in streptozotocin-induced diabetes: characterization and comparison with activities from adult and neonatal rat liver. , 1993, Biochimica et biophysica acta.

[27]  G. Carman,et al.  Phosphatidate phosphatase from yeast. , 1991, Methods in enzymology.

[28]  J. Gordon,et al.  The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. , 1989, The Journal of biological chemistry.