O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.
O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.
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DOI：
10.1016/j.cmet.2012.07.006
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发表时间：
2012-08-08
期刊：
影响因子：
29
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Ruan HB;Han X;Li MD;Singh JP;Qian K;Azarhoush S;Zhao L;Bennett AM;Samuel VT;Wu J;Yates JR 3rd;Yang X
糖尿病患者高血糖症的主要原因是不适当的肝脏再生。PGC-1α是胚胎发育的主要调控因子，其活性受多种翻译后修饰的调控。一小部分葡萄糖通过己糖胺生物合成途径代谢，导致细胞质和核蛋白的O-连接β-N-乙酰葡萄糖胺（O-GlcNAc）修饰。使用蛋白质组学方法，我们确定了各种各样的蛋白质与O-GlcNAc转移酶（OGT），其中宿主细胞因子C1（HCF-1）是非常丰富的。HCF-1将OGT募集为O-GlcNAc酰化PGC-1α，O-GlcNAc酰化促进去泛素化酶BAP 1的结合，从而保护PGC-1α免于降解并促进胚胎发育。葡萄糖利用率通过OGT/HCF 1复合物调节PGC-1α O-GlcNAc酰化和稳定性来调节胚胎发生。肝脏敲低OGT和HCF-1改善糖尿病小鼠的葡萄糖稳态。这些发现将OGT/HCF-1复合物定义为葡萄糖传感器和新生儿的关键调节因子，为治疗糖尿病的新策略提供了启示。
A major cause of hyperglycemia in diabetic patients is inappropriate hepatic gluconeogenesis. PGC-1α is a master regulator of gluconeogenesis, and its activity is controlled by various post-translational modifications. A small portion of glucose metabolizes through the hexosamine biosynthetic pathway, which leads to O-linked β-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins. Using a proteomic approach, we identified a broad variety of proteins associated with O-GlcNAc transferase (OGT), among which host cell factor C1 (HCF-1) is highly abundant. HCF-1 recruits OGT to O-GlcNAcylate PGC-1α and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1α from degradation and promoting gluconeogenesis. Glucose availability modulates gluconeogenesis through the regulation of PGC-1α O-GlcNAcylation and stability by the OGT/HCF1 complex. Hepatic knockdown of OGT and HCF-1 improves glucose homeostasis in diabetic mice. These findings define the OGT/HCF-1 complex as a glucose sensor and key regulator of gluconeogenesis, shedding light on new strategies for treating diabetes.
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影响因子：
14.8
作者：
Luo, Jinyong;Deng, Zhong-Liang;He, Tong-Chuan
通讯作者：
He, Tong-Chuan
DOI：
10.1073/pnas.152346899
发表时间：
2002-08-06
影响因子：
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作者：
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作者：
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作者：
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影响因子：
4.8
作者：
Housley, Michael P.;Udeshi, Namrata D.;Hart, Gerald W.
通讯作者：
Hart, Gerald W.