Citations 2
Identification of an intrinsic lysophosphatidic acid acyltransferase activity in the lipolytic inhibitor G 0 /G 1 switch gene 2 (G0S2)
Xie, Xitao, Heckmann, Bradlee L. , Saarinen, Alicia M., Gu, Haiwei , Liu, Jun , Liu, Jun , Zhang, Xiaodong , Zechner, Rudolf , Liu, Jun
The FASEB Journal | February 25, 2019 | Volume: 33 | Issue: 5 | Pages: 6655-6666
ABSTRACT G 0 /G 1 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 G 0 /G 1 switch gene 2 (G0S2). FASEB J. 33, 6655–6666 (2019). www.fasebj.org
Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression
Heckmann, Bradlee L. , Zhang, Xiaodong , Saarinen, Alicia M., Schoiswohl, Gabriele , Kershaw, Erin E. , Liu, Jun , Zechner, Rudolf , Liu, Jun , Liu, Jun
JCI Insight | February 16, 2017 | Volume: 2 | Issue: 4 | Pages: No page available
Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα. Transcriptional activation is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRα –/– mice exhibited decreased hepatic G0S2 expression, adenoviral expression of G0S2 was sufficient to restore fasting-induced TG storage and glycogen depletion in the liver of these mice. In response to LXR agonist T0901317, G0S2 ablation prevented hepatic steatosis and hypertriglyceridemia without affecting the beneficial effects on HDL. Thus, the LXRα-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR.