High glucose mediates the ChREBP/p300 transcriptional complex to activate proapoptotic genes Puma and BAX and contributes to intervertebral disc degeneration.

Abstract

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.

• Authors: Yu Feng, Hantao Wang, Zhi Chen, Bin Chen
• Journal: Bone (Bone) Vol. 153 Pg. 116164 (12 2021) ISSN: 1873-2763 [Electronic] United States
• PMID: 34461288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• bcl-2-Associated X Protein
• Glucose

Topics

• Animals
• Apoptosis (genetics)
• Apoptosis Regulatory Proteins (genetics)
• Diabetes Mellitus, Type 2
• Glucose
• Humans
• Intervertebral Disc
• Intervertebral Disc Degeneration (genetics)
• Rats
• bcl-2-Associated X Protein (genetics)