Nuclear Receptor Liver X Receptor Is O-GlcNAc-modified in Response to Glucose
Nuclear Receptor Liver X Receptor Is O-GlcNAc-modified in Response to Glucose
复制标题
DOI：
10.1074/jbc.m109.082685
复制
发表时间：
2010-01-15
影响因子：
4.8
通讯作者：
Gronning-Wang, Line M.
中科院分区：
文献类型：
--
作者：
Anthonisen, Elin Holter;Berven, Lise;Gronning-Wang, Line M.
在过去的25年中，通过O-连接的β-N-乙酰葡糖胺（O-GlcNAc）对核胞质蛋白的翻译后修饰已经成为一种重要的葡萄糖敏感机制。肝脏X受体（LXRs）作为营养传感器的胆固醇调节脂质代谢，葡萄糖稳态，炎症。LXR被证明是通过磷酸化、乙酰化和类小泛素化进行后修饰，分别影响其靶基因特异性、稳定性以及反式激活和反式抑制活性。在本研究中，我们首次表明LXR α和LXR β是人Huh 7细胞中葡萄糖-己糖胺衍生的O-GlcNAc修饰的靶点。此外，我们观察到增加肝脏LXR α O-GlcNAc酰化在体内的refed小鼠和链脲佐菌素诱导的refed糖尿病小鼠。重要的是，在两种小鼠模型中LXR α O-GlcNAc化的诱导伴随着脂肪生成基因SREBP-1c（固醇调节元件结合蛋白1c）表达的增加。此外，葡萄糖增加LXR/视黄酸受体依赖性激活的荧光素酶报告活性的小鼠SREBP-1c启动子通过己糖胺生物合成途径在Huh 7细胞驱动。总之，我们的研究结果表明，LXR的O-GlcNAc酰化是一种新的机制，LXR作为葡萄糖传感器影响LXR依赖的基因表达，证实了LXR作为营养传感器在脂质和葡萄糖代谢中的关键作用。
Post-translational modification of nucleocytoplasmic proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) has for the last 25 years emerged as an essential glucose-sensing mechanism. The liver X receptors (LXRs) function as nutritional sensors for cholesterol-regulating lipid metabolism, glucose homeostasis, and inflammation. LXRs are shown to be posttranslationally modified by phosphorylation, acetylation, and sumoylation, affecting their target gene specificity, stability, and transactivating and transrepressional activity, respectively. In the present study, we show for the first time that LXR alpha and LXR beta are targets for glucose-hexosamine-derived O-GlcNAc modification in human Huh7 cells. Furthermore, we observed increased hepatic LXR alpha O-GlcNAcylation in vivo in refed mice and in streptozotocin-induced refed diabetic mice. Importantly, induction of LXR alpha O-GlcNAcylation in both mouse models was concomitant with increased expression of the lipogenic gene SREBP-1c (sterol regulatory element-binding protein 1c). Furthermore, glucose increased LXR/retinoic acid receptor-dependent activation of luciferase reporter activity driven by the mouse SREBP-1c promoter via the hexosamine biosynthetic pathway in Huh7 cells. Altogether, our results suggest that O-GlcNAcylation of LXR is a novel mechanism by which LXR acts as a glucose sensor affecting LXR-dependent gene expression, substantiating the crucial role of LXR as a nutritional sensor in lipid and glucose metabolism.