The function and regulation of the G0/G1 Switch Gene 2 (G0S2).

摘要

Evidence from our laboratory has established a role for the G0/G1 Switch Gene 2 (G0S2) as the primary inhibitor of adipose lipolysis through inhibition of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triglyceride hydrolysis. To determine the physiological role of G0S2 and its ability to inhibit ATGL in vivo, we constructed an adipose tissue-specific G0S2 transgenic mouse model (aP2-G0S2). In response to fasting or beta3-adrenergic receptor activation, in vivo lipolysis and ketogenesis were decreased in G0S2 transgenic mice when compared to wild type animals. Due to decreased lipolysis, adipose overexpression of G0S2 prevented the energy substrate "switch" from carbohydrates to fatty acids (FAs) during fasting known as the adaptive energy response. Interestingly, even with increased adiposity, aP2-G0S2 mice had improved insulin sensitivity. These results indicate that fat-specific G0S2 overexpression uncouples adiposity from insulin sensitivity and overall metabolic health through inhibiting adipose lipolysis, decreasing circulating FAs, and reducing hepatic TG accumulation. Consistent with this, inhibition of lipolysis resulted in mitigation of fasting-induced expression of G0S2 in liver. Since G0S2 levels are dynamically linked and rapidly responsive to nutrient status or metabolic requirements, the identification of its expression regulation is of meaningful value. Earlier evidence from our laboratory demonstrated that G0S2 is a short-lived protein degraded through the proteasomal pathway. We demonstrate that protein degradation is initiated by K48-linked polyubiquitination of the lysine-25 in G0S2 and G0S2 protein is stabilized in response to ATGL expression and/or TG accumulation. Likewise FAs have been linked to the transcriptional regulation of G0S2. LXRalpha has been implicated in regulating hepatic TG accumulation upon both influx of adipose-derived FAs during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. Here, we show that G0S2 is a direct target gene of LXRalpha. Transcriptional activation is conferred by LXRalpha binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRalpha knockout mice exhibited a decreased hepatic G0S2 expression and TG content, adenoviral expression of G0S2 was sufficient to restore fasting-induced TG storage and glycogen depletion in the livers of these mice. In response to LXR agonist T0901317, G0S2 ablation prevented hepatic steatosis and hypertriglyceridemia without affecting the beneficial effects on cholesterol metabolism. Thus, the LXRalpha-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR, establishing a unified mechanism for regulating TG accumulation. Cumulatively, our data demonstrates a multifaceted regulation and function of G0S2 that has significant importance to global lipid metabolism and energy homeostasis.