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

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). FASEB J. 33, 6655–6666 (2019). http://www.fasebj.org

Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes

“…HILPDA and G0S2 share extensive sequence homology, and both proteins are able to inhibit ATGL. Recently, evidence was provided that G0S2 not only suppresses lipolysis but also promotes triglyceride synthesis by carrying glycerol-3-phosphate acyltransferase (GPAT/LPAAT/AGPAT) enzymatic activity [ 39 ]. Given the very small size of HILPDA (63 amino acids), it is unlikely that HILPDA can itself function as a fatty acid esterification enzyme.…”

Bioinformatic Analysis and Biophysical Characterization Reveal Structural Disorder in G0S2 Protein

“…Moreover, the G 0 S 2 gene is upregulated by the lipogenic transcription factor liver X receptor α. 7 In addition, the G 0 S 2 gene has been found to be hypermethylated in certain types of cancer, indicating a possible role in cancer development. 4 , 8 …”

Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease

“…This study showed that G0S2 is a component for regulation in lipolysis, implicating it as potential target in the treatment of obesity and diabetes related conditions such as NAFLD [12][13][14]. Other studies have revealed several additional potential functions of G0S2 in lymphocyte activation, proliferation of leukemia cells, promotion of apoptosis, and reduction of tumor growth [15][16][17][18][19].…”