Liver X receptor ? mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression.

ABSTRACT: Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXR? 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 LXR?. Transcriptional activation is conferred by LXR? binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXR?^-/- 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 LXR?-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR.

SUBMITTER: Heckmann BL 

PROVIDER: S-EPMC5313069 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature