GPAT3 and GPAT4 Are Regulated by Insulin-stimulated Phosphorylation and Play Distinct Roles in Adipogenesis

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2010 Feb 26

PMID 20181984

Citations 52

Authors

Dandan Shan

Jian-Liang Li

Leeying Wu

Dongmei Li

Jonathan Hurov

James F Tobin

Ruth E Gimeno

Jingsong Cao

Affiliations

Soon will be listed here.

Abstract

Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step during de novo synthesis of glycerolipids. Mammals have at least four GPAT isoforms. Here we report the further characterization of the two recently identified microsomal GPAT3 and GPAT4. Both enzymes are highly expressed in adipose tissues. However, while GPAT3 is highly (approximately 60-fold) induced during adipocyte differentiation, GPAT4 induction is only modest (approximately 5-fold), leading to a lower abundance of GPAT4 mRNA in adipocytes. While overexpression of GPAT3 and GPAT4 in either insect or mammalian cells results in a comparable increase of GPAT activity, shRNA-mediated knockdown of GPAT3, but not GPAT4, in 3T3-L1 adipocytes led to a significant decrease in GPAT activity, a profound inhibition of lipid accumulation, and a lack of expression of several adipogenic markers during adipocyte differentiation. These data suggest that GPAT3 may encode the major GPAT isoform in adipocytes and play an important role in adipogenesis. Furthermore, we have shown that both GPAT3 and GPAT4 are phosphorylated by insulin at Ser and Thr residues, leading to increased GPAT activity that is sensitive to wortmannin. Our results reveal a link between the lipogenic effects of insulin and microsomal GPAT3 and GPAT4, implying their importance in glycerolipid biosynthesis.

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References

Beigneux A, Vergnes L, Qiao X, Quatela S, Davis R, Watkins S . Agpat6--a novel lipid biosynthetic gene required for triacylglycerol production in mammary epithelium. J Lipid Res. 2006; 47(4):734-44. PMC: 3196597. DOI: 10.1194/jlr.M500556-JLR200. View

Gutierrez J, Solenberg P, Perkins D, Willency J, Knierman M, Jin Z . Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A. 2008; 105(17):6320-5. PMC: 2359796. DOI: 10.1073/pnas.0800708105. View

Huffman T, Mothe-Satney I, Lawrence Jr J . Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci U S A. 2002; 99(2):1047-52. PMC: 117427. DOI: 10.1073/pnas.022634399. View

Yet S, Lee S, Hahm Y, Sul H . Expression and identification of p90 as the murine mitochondrial glycerol-3-phosphate acyltransferase. Biochemistry. 1993; 32(36):9486-91. DOI: 10.1021/bi00087a029. View

Coleman R, Reed B, Mackall J, Student A, Lane M, Bell R . Selective changes in microsomal enzymes of triacylglycerol phosphatidylcholine, and phosphatidylethanolamine biosynthesis during differentiation of 3T3-L1 preadipocytes. J Biol Chem. 1978; 253(20):7256-61. View

Saggerson E, Carpenter C . Effects of streptozotocin-diabetes and insulin administration in vivo or in vitro on the activities of five enzymes in the adipose-tissue triacylglycerol-synthesis pathway. Biochem J. 1987; 243(1):289-92. PMC: 1147847. DOI: 10.1042/bj2430289. View

Moolenaar W . Lysophosphatidic acid, a multifunctional phospholipid messenger. J Biol Chem. 1995; 270(22):12949-52. DOI: 10.1074/jbc.270.22.12949. View

Cao J, Burn P, Shi Y . Properties of the mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J Biol Chem. 2003; 278(28):25657-63. DOI: 10.1074/jbc.M302835200. View

Gale S, Frolov A, Han X, Bickel P, Cao L, Bowcock A . A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation. J Biol Chem. 2006; 281(16):11082-9. DOI: 10.1074/jbc.M509612200. View

10.

Vila M, Farese R . Insulin rapidly increases glycerol-3-phosphate-acyltransferase activity in rat adipocytes. Arch Biochem Biophys. 1991; 284(2):366-8. DOI: 10.1016/0003-9861(91)90309-7. View

11.

Lewin T, de Jong H, Schwerbrock N, Hammond L, Watkins S, Combs T . Mice deficient in mitochondrial glycerol-3-phosphate acyltransferase-1 have diminished myocardial triacylglycerol accumulation during lipogenic diet and altered phospholipid fatty acid composition. Biochim Biophys Acta. 2008; 1781(6-7):352-8. PMC: 3285559. DOI: 10.1016/j.bbalip.2008.05.001. View

12.

Cao J, Liu Y, Lockwood J, Burn P, Shi Y . A novel cardiolipin-remodeling pathway revealed by a gene encoding an endoplasmic reticulum-associated acyl-CoA:lysocardiolipin acyltransferase (ALCAT1) in mouse. J Biol Chem. 2004; 279(30):31727-34. DOI: 10.1074/jbc.M402930200. View

13.

Lewin T, Wang P, Coleman R . Analysis of amino acid motifs diagnostic for the sn-glycerol-3-phosphate acyltransferase reaction. Biochemistry. 1999; 38(18):5764-71. DOI: 10.1021/bi982805d. View

14.

Cao J, Li J, Li D, Tobin J, Gimeno R . Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis. Proc Natl Acad Sci U S A. 2006; 103(52):19695-700. PMC: 1702318. DOI: 10.1073/pnas.0609140103. View

15.

Lewin T, Schwerbrock N, Lee D, Coleman R . Identification of a new glycerol-3-phosphate acyltransferase isoenzyme, mtGPAT2, in mitochondria. J Biol Chem. 2004; 279(14):13488-95. DOI: 10.1074/jbc.M314032200. View

16.

Vila M, Milligan G, Standaert M, Farese R . Insulin activates glycerol-3-phosphate acyltransferase (de novo phosphatidic acid synthesis) through a phospholipid-derived mediator. Apparent involvement of Gi alpha and activation of a phospholipase C. Biochemistry. 1990; 29(37):8735-40. DOI: 10.1021/bi00489a033. View

17.

Cao J, Shan D, Revett T, Li D, Wu L, Liu W . Molecular identification of a novel mammalian brain isoform of acyl-CoA:lysophospholipid acyltransferase with prominent ethanolamine lysophospholipid acylating activity, LPEAT2. J Biol Chem. 2008; 283(27):19049-57. DOI: 10.1074/jbc.M800364200. View

18.

Agarwal A, Arioglu E, de Almeida S, Akkoc N, Taylor S, Bowcock A . AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002; 31(1):21-3. DOI: 10.1038/ng880. View

19.

Chen Y, Kuo M, Li S, Bui H, Peake D, Sanders P . AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase. J Biol Chem. 2008; 283(15):10048-57. PMC: 2442282. DOI: 10.1074/jbc.M708151200. View

20.

Yuki K, Shindou H, Hishikawa D, Shimizu T . Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis. J Lipid Res. 2008; 50(5):860-9. PMC: 2666172. DOI: 10.1194/jlr.M800468-JLR200. View