The discovery of the fat-regulating phosphatidic acid phosphatase gene

Abstract

Phosphatidic acid phosphatase is a fat-regulating enzyme that plays a major role in controlling the balance of phosphatidic acid (substrate) and diacylglycerol (product), which are lipid precursors used for the synthesis of membrane phospholipids and triacylglycerol. Phosphatidic acid is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, secretion, and endocytosis. While this important enzyme has been known for several decades, its gene was only identified recently from yeast. This discovery showed the importance of phosphatidic acid phosphatase in lipid metabolism in yeast as well as in higher eukaryotes including humans.

Key words： phosphatidic acid phosphatase; yeast; lipin; phospholipid; triacylglycerol

Acknowledgements

This review is dedicated to the Carman laboratory members who have worked on the PA phosphatase enzyme. I also thank Gil-Soo Han for the critical reading of this manuscript. This work was supported in part by National Institutes of Health Grant GM-28140.

References

1 Carman G M, Han G S (2006). Roles of phosphatidate phosphatase enzymes in lipid metabolism. Trends Biochem Sci, 31(12): 694–699

PMID

2 Carman G M, Han G S (2009). Phosphatidic acid phosphatase, a key enzyme in the regulation of lipid synthesis. J Biol Chem, 284(5): 2593–2597

PMID

3 Carman G M, Henry S A (1999). Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes. Prog Lipid Res, 38(5-6): 361–399

PMID

4 Carman G M, Henry S A (2007). Phosphatidic acid plays a central role in the transcriptional regulation of glycerophospholipid synthesis in Saccharomyces cerevisiae. J Biol Chem, 282(52): 37293–37297

PMID

5 Csaki L S, Reue K (2010). Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr, 30(1): 257–272

PMID

6 Donkor J, Sariahmetoglu M, Dewald J, Brindley D N, Reue K (2007). Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns. J Biol Chem, 282(6): 3450–3457

PMID

7 Donkor J, Zhang P, Wong S, O’Loughlin L, Dewald J, Kok B P, Brindley D N, Reue K (2009). A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. J Biol Chem, 284(43): 29968–29978

PMID

8 Finck B N, Gropler M C, Chen Z, Leone T C, Croce M A, Harris T E, Lawrence J C Jr, Kelly D P (2006). Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab, 4(3): 199–210

PMID

9 Han G S, Carman G M (2010). Characterization of the human LPIN1-encoded phosphatidate phosphatase isoforms. J Biol Chem, 285(19): 14628–14638

PMID

10 Han G S, Siniossoglou S, Carman G M (2007). The cellular functions of the yeast lipin homolog PAH1p are dependent on its phosphatidate phosphatase activity. J Biol Chem, 282(51): 37026–37035

PMID

11 Han G S, Wu W I, Carman G M (2006). The Saccharomyces cerevisiae Lipin homolog is a Mg²⁺-dependent phosphatidate phosphatase enzyme. J Biol Chem, 281(14): 9210–9218

PMID

12 Irie K, Takase M, Araki H, Oshima Y (1993). A gene, SMP2, involved in plasmid maintenance and respiration in Saccharomyces cerevisiae encodes a highly charged protein. Mol Gen Genet, 236(2-3): 283–288

PMID

13 Koh Y K, Lee M Y, Kim J W, Kim M, Moon J S, Lee Y J, Ahn Y H, Kim K S (2008). Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma 2. J Biol Chem, 283(50): 34896–34906

PMID

14 Koonin E V, Tatusov R L (1994). Computer analysis of bacterial haloacid dehalogenases defines a large superfamily of hydrolases with diverse specificity. Application of an iterative approach to database search. J Mol Biol, 244(1): 125–132

PMID

15 Langner C A, Birkenmeier E H, Ben-Zeev O, Schotz M C, Sweet H O, Davisson M T, Gordon J I (1989). 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. J Biol Chem, 264(14): 7994–8003

PMID

16 Langner C A, Birkenmeier E H, Roth K A, Bronson R T, Gordon J I (1991). Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J Biol Chem, 266(18): 11955–11964

PMID

17 Lin Y P, Carman G M (1989). Purification and characterization of phosphatidate phosphatase from Saccharomyces cerevisiae. J Biol Chem, 264(15): 8641–8645

PMID

18 Lin Y P, Carman G M (1990). Kinetic analysis of yeast phosphatidate phosphatase toward Triton X-100/phosphatidate mixed micelles. J Biol Chem, 265(1): 166–170

PMID

19 Loewen C J R, Gaspar M L, Jesch S A, Delon C, Ktistakis N T, Henry S A, Levine T P (2004). Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science, 304(5677): 1644–1647

PMID

20 Madera M, Vogel C, Kummerfeld S K, Chothia C, Gough J (2004). The SUPERFAMILY database in 2004: additions and improvements. Nucleic Acids Res, 32(90001 Database issue): D235–D239

PMID

21 Nadra K, de Preux Charles A S, Médard J J, Hendriks W T, Han G S, Grès S, Carman G M, Saulnier-Blache J S, Verheijen M H, Chrast R (2008). Phosphatidic acid mediates demyelination in Lpin1 mutant mice. Genes Dev, 22(12): 1647–1661

PMID

22 Péterfy M, Phan J, Reue K (2005). Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem, 280(38): 32883–32889

PMID

23 Péterfy M, Phan J, Xu P, Reue K (2001). Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet, 27(1): 121–124

PMID

24 Phan J, Reue K (2005). Lipin, a lipodystrophy and obesity gene. Cell Metab, 1(1): 73–83

PMID

25 Reue K, Brindley D N (2008). Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J Lipid Res, 49(12): 2493–2503

PMID

26 Reue K, Donkor J (2007). Genetic factors in type 2 diabetes: all in the (lipin) family. Diabetes, 56(12): 2842–2843

PMID

27 Reue K, Dwyer J R (2009). Lipin proteins and metabolic homeostasis. J Lipid Res, 50(Suppl): S109–S114

PMID

28 Reue K, Zhang P (2008). The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett, 582(1): 90–96

PMID

29 Santos-Rosa H, Leung J, Grimsey N, Peak-Chew S, Siniossoglou S (2005). The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth. EMBO J, 24(11): 1931–1941

PMID

30 Siniossoglou S (2009). Lipins, lipids and nuclear envelope structure. Traffic, 10(9): 1181–1187

PMID

31 Siniossoglou S, Santos-Rosa H, Rappsilber J, Mann M, Hurt E (1998). A novel complex of membrane proteins required for formation of a spherical nucleus. EMBO J, 17(22): 6449–6464

PMID

32 Smith S W, Weiss S B, Kennedy E P (1957). The enzymatic dephosphorylation of phosphatidic acids. J Biol Chem, 228(2): 915–922

PMID

33 Wu W I, Carman G M (1994). Regulation of phosphatidate phosphatase activity from the yeast Saccharomyces cerevisiae by nucleotides. J Biol Chem, 269(47): 29495–29501

PMID

34 Wu W I, Carman G M (1996). Regulation of phosphatidate phosphatase activity from the yeast Saccharomyces cerevisiae by phospholipids. Biochemistry, 35(12): 3790–3796

PMID

35 Wu W I, Lin Y P, Wang E, Merrill A H Jr, Carman G M (1993). Regulation of phosphatidate phosphatase activity from the yeast Saccharomyces cerevisiae by sphingoid bases. J Biol Chem, 268(19): 13830–13837

PMID