TY - JOUR
T1 - Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 switch gene 2 expression
AU - Heckmann, Bradlee L.
AU - Zhang, Xiaodong
AU - Saarinen, Alicia M.
AU - Schoiswohl, Gabriele
AU - Kershaw, Erin E.
AU - Zechner, Rudolf
AU - Liu, Jun
N1 - Funding Information:
We would like to thank the Vanderbilt Hormone Assay Core facility for their expertise in lipid/FA profiling. We would also like to thank Changcheng Zhou (University of Kentucky) and Xitao Xie (Arizona State University) for critical discussions. This work was supported by research grants from the NIH (DK089178 and DK109096) to JL, NIH (DK090166) to EEK, as well as predoctoral funding to BLH from the Mayo Foundation for Medical Education & Research.
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/2/23
Y1 - 2017/2/23
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.88735
DO - 10.1172/jci.insight.88735
M3 - Article
AN - SCOPUS:85028916013
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 4
M1 - e88735
ER -