Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G 0 /G 1 switch gene 2 (G0S2)

Xiaodong Zhang, Xitao Xie, Bradlee L. Heckmann, Alicia M. Saarinen, Haiwei Gu, Rudolf Zechner, Jun D Liu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

G0/G1 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 via 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 in vitro and in vivo. 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 G0/G1 switch gene 2 (G0S2).

Original languageEnglish (US)
Pages (from-to)6655-6666
Number of pages12
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Switch Genes
Genes
Switches
Triglycerides
Liver
Lipase
Lipolysis
2-acylglycerophosphate acyltransferase
Acyltransferases
Acyl Coenzyme A
Phosphatidic Acids
Gene encoding
Diglycerides
Enzymes
Nutrition
Ablation
Lipid Metabolism
Sucrose
Hepatocytes
Transcription Factors

Keywords

  • fatty liver disease
  • hepatic steatosis
  • lipogenesis
  • lipolysis
  • LPA acyltransferase

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G 0 /G 1 switch gene 2 (G0S2) . / Zhang, Xiaodong; Xie, Xitao; Heckmann, Bradlee L.; Saarinen, Alicia M.; Gu, Haiwei; Zechner, Rudolf; Liu, Jun D.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 5, 01.05.2019, p. 6655-6666.

Research output: Contribution to journalArticle

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AU - Zhang, Xiaodong

AU - Xie, Xitao

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AU - Saarinen, Alicia M.

AU - Gu, Haiwei

AU - Zechner, Rudolf

AU - Liu, Jun D

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AB - G0/G1 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 via 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 in vitro and in vivo. 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 G0/G1 switch gene 2 (G0S2).

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