High glucose mediates the ChREBP/p300 transcriptional complex to activate proapoptotic genes Puma and BAX and contributes to intervertebral disc degeneration
High glucose mediates the ChREBP/p300 transcriptional complex to activate proapoptotic genes Puma and BAX and contributes to intervertebral disc degeneration
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DOI：
10.1016/j.bone.2021.116164
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发表时间：
2021-09-02
期刊：
影响因子：
4.1
通讯作者：
Chen, Bin
中科院分区：
文献类型：
--
作者：
Feng, Yu;Wang, Hantao;Chen, Bin
新证据表明，肥胖和 2 型糖尿病 (T2D) 与椎间盘退变 (IDD) 相关。然而，潜在的机制仍然不清楚。在这里，我们发现 T2D-IDD 患者的血清葡萄糖浓度显着升高。分子变化检测表明，在这些肥胖 IDD 患者中，包括 GLUT1 和 GLUT4 在内的两种葡萄糖转运蛋白 (GLUT) 过度激活。使用微阵列检测来检测肥胖 IDD 患者的失调基因，我们鉴定了 33 个差异表达基因，并仅验证了两个促凋亡基因，包括 Puma（p53 上调的细胞凋亡调节剂）和 BAX（BCL2 相关 X）对葡萄糖有反应。机制研究表明，碳水化合物反应元件结合蛋白（ChREBP）与组蛋白乙酰转移酶p300偶联，结合到Puma和BAX基因的启动子上，并在高葡萄糖条件下激活它们的表达。 Puma 和 BAX 的积累引发线粒体功能障碍和 caspase 激活，导致细胞凋亡。此外，我们发现葡萄糖可以加速大鼠模型中 IDD 的发生。有趣的是，我们给注射葡萄糖的大鼠注射了两种GLUT抑制剂（BAY-876和Fasentin），发现这两种抑制剂可以通过减少细胞凋亡来逆转IDD的缺陷。我们的体外和体内数据支持一个模型，其中高葡萄糖激活 ChREBP/p300 转录复合物与 Puma 和 BAX 的启动子结合，导致细胞凋亡和 IDD 发病机制。我们的发现表明，控制 T2D-IDD 患者的葡萄糖吸收可能会降低 IDD 的结果。
Emerging evidence shows that obesity and type 2 diabetes (T2D) are associated with intervertebral disc degeneration (IDD). However, the underlying mechanisms are still obscure. Here, we found that serum glucose concentrations were significantly increased in T2D-IDD patients. Detection of molecular changes indicated that two glucose transporters (GLUTs), including GLUT1 and GLUT4, were hyperactivated in these IDD patients with obesity. Using a microarray assay to detect the dysregulated genes in IDD patients with obesity, we identified 33 differentially expressed genes and verified only two proapoptotic genes, including Puma (p53 upregulated modulator of apoptosis) and BAX (BCL2 associated X) responded to glucose. The mechanistic investigation revealed that carbohydrate-responsive element-binding protein (ChREBP) coupled with the histone acetyltransferase p300 to bind to the promoter of Puma and BAX genes and activated their expression in the condition of high glucose. The accumulation of Puma and BAX triggered mitochondrial dysfunction and caspase activation, resulting in apoptosis. Moreover, we found that glucose could accelerate the occurrence of IDD in a rat model. Interestingly, we administrated two GLUT inhibitors (BAY-876 and Fasentin) in rats injected glucose and found that these two inhibitors could reverse the defects of IDD by decreasing apoptosis. Our in vitro and in vivo data support a model in which high glucose activates the ChREBP/p300 transcriptional complex to bind to the promoters of Puma and BAX, causing apoptosis and IDD pathogenesis. Our discovery suggests that the control of glucose absorption in T2D-IDD patients may decrease the outcome of IDD.