Chung Sung Soo, Kim Ji Hyun, Park Ho Seon, Choi Hye Hun, Lee Kyeong Won, Cho Young Min, Lee Hong Kyu, Park Kyong Soo
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea.
Biochem Biophys Res Commun. 2008 Aug 8;372(4):713-8. doi: 10.1016/j.bbrc.2008.05.096. Epub 2008 May 28.
O-GlcNAcylation is a kind of post-translational modification and many nuclear and cytoplasmic proteins are O-GlcNAcylated. In this study, we demonstrated that thiazolidinediones (TZDs), which are used as insulin sensitizer, specifically inhibited the O-GlcNAcylation of Sp1 but did not affect the O-GlcNAcylation of the total proteins in cell culture systems and mouse models. This effect was mediated by peroxisome proliferator activated receptor gamma (PPARgamma) activation and probably by synthesis of a specific protein induced by PPARgamma activation. In addition, we demonstrated that the O-GlcNAcylation sites in the zinc-finger domain were involved in the transcriptional activation of Sp1 and that rosiglitazone, a member of TZDs, affected Sp1 transcriptional activity partially by regulating the O-GlcNAcylation level of these sites. Considering the role of hexosamine biosynthesis pathway in hyperglycemia-induced insulin resistance and Sp1 in the hyperglycemia-induced gene expression, the regulation of Sp1 O-GlcNAcylation by TZDs may help to explain the function of TZDs as a treatment for insulin resistance and diabetes.
O-连接的N-乙酰葡糖胺化是一种翻译后修饰，许多核蛋白和胞质蛋白都发生了O-连接的N-乙酰葡糖胺化。在本研究中，我们证明，作为胰岛素增敏剂的噻唑烷二酮类药物（TZDs）在细胞培养系统和小鼠模型中特异性抑制Sp1的O-连接的N-乙酰葡糖胺化，但不影响总蛋白的O-连接的N-乙酰葡糖胺化。这种效应是由过氧化物酶体增殖物激活受体γ（PPARγ）激活介导的，可能还与PPARγ激活诱导的一种特定蛋白质的合成有关。此外，我们证明锌指结构域中的O-连接的N-乙酰葡糖胺化位点参与了Sp1的转录激活，并且噻唑烷二酮类药物之一的罗格列酮通过调节这些位点的O-连接的N-乙酰葡糖胺化水平部分影响Sp1的转录活性。考虑到己糖胺生物合成途径在高血糖诱导的胰岛素抵抗中的作用以及Sp1在高血糖诱导的基因表达中的作用，TZDs对Sp1的O-连接的N-乙酰葡糖胺化的调节可能有助于解释TZDs作为胰岛素抵抗和糖尿病治疗药物的作用机制。
