Liver X receptor α mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression
Bradlee L. Heckmann, … , Rudolf Zechner, Jun Liu
Bradlee L. Heckmann, … , Rudolf Zechner, Jun Liu
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e88735. https://doi.org/10.1172/jci.insight.88735.
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Research Article Hepatology Metabolism

Liver X receptor α 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. 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.

Authors

Bradlee L. Heckmann, Xiaodong Zhang, Alicia M. Saarinen, Gabriele Schoiswohl, Erin E. Kershaw, Rudolf Zechner, Jun Liu

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Figure 5

LXRα regulates G0S2 expression through direct promoter binding.

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LXRα regulates G0S2 expression through direct promoter binding. (A) Sequ...
(A) Sequence alignment of the putative DR4/LXRE identified in the proximal G0S2 promoter across species. Twelve-week-old female WT mice were either fasted for 16 hours or injected with vehicle or T0901317 as described previously. Hepatic lysate was then subjected to ChIP. (B) qPCR analysis of LXRα-specific ChIP chromatin from fed and fasted mice. (C) qPCR analysis of LXRα-specific ChIP chromatin from T09-injected mice. (D) qPCR analysis of LXRβ-specific ChIP chromatin from T09-injected mice. For panels B–D, primer sets against the putative G0S2 –2 kbDR4 LXRE, the G0S2 5′ and 3′ flanking regions, positive control LXREs, and a negative control were used. Data is represented as % of input of fed vs. fasted or vehicle vs. T09. (E) EMSA assays were performed for G0S2 LXRE binding to LXRα and LXRβ in the presence or absence of RXRα. Specific and nonspecific competitors were used as shown. (F) Schematic showing the promoter regions of G0S2 cloned into the pGL4 luciferase reporter system. Cotransfection assays with LXRα/RXRα in the presence or absence of 10 μM T09 or 0.725 mM C18:2 and 5 μM HX531 were conducted in HeLa cells. (G) Luciferase expression in the presence or absence of T09. (H) Luciferase expression in the presence of absence of linoleic acid (FA) and HX531. (n = 4 for ChIP performed in duplicate, n = 3 for luciferase assays performed in duplicate; **P < 0.01, ***P < 0.001, Student’s t test.)