Identification of an Intrinsic Lysophosphatidic Acid Acyltransferase Activity in the Lipolytic Inhibitor G/G Switch Gene 2 (G0S2)

Overview

Journal FASEB J

Specialties Biology
Physiology

Date 2019 Feb 26

PMID 30802154

Citations 11

Authors

Xiaodong Zhang

Xitao Xie

Bradlee L Heckmann

Alicia M Saarinen

Haiwei Gu

Rudolf Zechner

Jun Liu

Affiliations

Soon will be listed here.

Abstract

G/G switch gene 2 (G0S2) is a specific inhibitor of adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis. Recent studies show that G0S2 plays a critical role in promoting triacylglycerol (TG) accumulation in the liver, and its encoding gene is a direct target of a major lipogenic transcription factor liver X receptor (LXR)α. Here we sought to investigate a lipolysis-independent role of G0S2 in hepatic triglyceride synthesis. Knockdown of G0S2 decreased hepatic TG content in mice with ATGL ablation. Conversely, overexpression of G0S2 promoted fatty acid incorporation into TGs and diacylglycerols in both wild-type and ATGL-deficient hepatocytes. Biochemical characterization showed that G0S2 mediates phosphatidic acid synthesis from lysophosphatidic acid (LPA) and acyl-coenzyme A. In response to a high-sucrose lipogenic diet, G0S2 is up-regulated LXRα and required for the increased TG accumulation in liver. Furthermore, deletion of a distinct 4-aa motif necessary for the LPA-specific acyltransferase (LPAAT) activity impaired G0S2's ability to mediate TG synthesis both and . These studies identify G0S2 as a dual-function regulator of lipid metabolism as well as a novel mechanism whereby hepatic TG storage is promoted in response to lipogenic stimulation. In addition to its role as a lipolytic inhibitor, G0S2 is capable of directly promoting TG synthesis by acting as a lipid-synthesizing enzyme.-Zhang, X., Xie, X., Heckmann, B. L., Saarinen, A. M., Gu, H., Zechner, R., Liu, J. Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G/G switch gene 2 (G0S2).

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References

Heckmann B, Zhang X, Saarinen A, Schoiswohl G, Kershaw E, Zechner R . Liver X receptor mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression. JCI Insight. 2017; 2(4):e88735. PMC: 5313069. DOI: 10.1172/jci.insight.88735. View

Yamashita A, Hayashi Y, Matsumoto N, Nemoto-Sasaki Y, Oka S, Tanikawa T . Glycerophosphate/Acylglycerophosphate acyltransferases. Biology (Basel). 2014; 3(4):801-30. PMC: 4280512. DOI: 10.3390/biology3040801. View

Eberhardt C, Gray P, Tjoelker L . Human lysophosphatidic acid acyltransferase. cDNA cloning, expression, and localization to chromosome 9q34.3. J Biol Chem. 1997; 272(32):20299-305. DOI: 10.1074/jbc.272.32.20299. View

Zechner R, Zimmermann R, Eichmann T, Kohlwein S, Haemmerle G, Lass A . FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012; 15(3):279-91. PMC: 3314979. DOI: 10.1016/j.cmet.2011.12.018. View

Schreiber R, Hofer P, Taschler U, Voshol P, Rechberger G, Kotzbeck P . Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity. Proc Natl Acad Sci U S A. 2015; 112(45):13850-5. PMC: 4653216. DOI: 10.1073/pnas.1516004112. View

Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J . Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006; 312(5774):734-7. DOI: 10.1126/science.1123965. View

Chen G, Liang G, Ou J, Goldstein J, Brown M . Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A. 2004; 101(31):11245-50. PMC: 509189. DOI: 10.1073/pnas.0404297101. View

Barrows B, Timlin M, Parks E . Spillover of dietary fatty acids and use of serum nonesterified fatty acids for the synthesis of VLDL-triacylglycerol under two different feeding regimens. Diabetes. 2005; 54(9):2668-73. DOI: 10.2337/diabetes.54.9.2668. View

El-Assaad W, El-Kouhen K, Mohammad A, Yang J, Morita M, Gamache I . Deletion of the gene encoding G0/G 1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice. Diabetologia. 2014; 58(1):149-57. PMC: 5001162. DOI: 10.1007/s00125-014-3429-z. View

10.

Cornaciu I, Boeszoermenyi A, Lindermuth H, Nagy H, Cerk I, Ebner C . The minimal domain of adipose triglyceride lipase (ATGL) ranges until leucine 254 and can be activated and inhibited by CGI-58 and G0S2, respectively. PLoS One. 2011; 6(10):e26349. PMC: 3198459. DOI: 10.1371/journal.pone.0026349. View

11.

Anthonisen E, Berven L, Holm S, Nygard M, Nebb H, Gronning-Wang L . Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose. J Biol Chem. 2009; 285(3):1607-15. PMC: 2804318. DOI: 10.1074/jbc.M109.082685. View

12.

Malhi H, Gores G . Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008; 28(4):360-9. PMC: 2908270. DOI: 10.1055/s-0028-1091980. View

13.

Jenkins C, Mancuso D, Yan W, Sims H, Gibson B, Gross R . Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem. 2004; 279(47):48968-75. DOI: 10.1074/jbc.M407841200. View

14.

Liu J, Deyoung S, Zhang M, Dold L, Saltiel A . The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. J Biol Chem. 2005; 280(16):16125-34. DOI: 10.1074/jbc.M500940200. View

15.

Cortes V, Curtis D, Sukumaran S, Shao X, Parameswara V, Rashid S . Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab. 2009; 9(2):165-76. PMC: 2673980. DOI: 10.1016/j.cmet.2009.01.002. View

16.

Green C, Pramfalk C, Morten K, Hodson L . From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations. Am J Physiol Endocrinol Metab. 2014; 308(1):E1-20. PMC: 4281685. DOI: 10.1152/ajpendo.00192.2014. View

17.

Hollenback D, Bonham L, Law L, Rossnagle E, Romero L, Carew H . Substrate specificity of lysophosphatidic acid acyltransferase beta -- evidence from membrane and whole cell assays. J Lipid Res. 2005; 47(3):593-604. DOI: 10.1194/jlr.M500435-JLR200. 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.

Wu J, Wang S, Alvarez F, Casavant S, Gauthier N, Abed L . Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology. 2011; 54(1):122-32. DOI: 10.1002/hep.24338. View

20.

Schweiger M, Paar M, Eder C, Brandis J, Moser E, Gorkiewicz G . G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase. J Lipid Res. 2012; 53(11):2307-17. PMC: 3466000. DOI: 10.1194/jlr.M027409. View