Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, China.
FEBS Open Bio. 2024 Nov;14(11):1864-1872. doi: 10.1002/2211-5463.13900. Epub 2024 Sep 19.
SNAP25 plays an essential role in the glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells. Carbohydrate response element-binding protein (ChREBP) is an important transcription factor in β-cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in β-cells. We show that diabetic Goto-Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in β-cells, while SNAP25 overexpression increased GSIS in β-cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in β-cells and suggest that SNAP25 may be involved in the regulation of β-cell secretory function controlled by ChREBP.
突触融合蛋白 25（SNAP25）在胰岛β细胞的葡萄糖刺激的胰岛素分泌（GSIS）中发挥着重要作用。碳水化合物反应元件结合蛋白（ChREBP）是β细胞中的一个重要转录因子，在本研究中，我们旨在探讨 ChREBP 是否调节β细胞中的 SNAP25 表达。我们发现，糖尿病 Goto-Kakizaki（GK）大鼠表现出胰岛素分泌受损和高血糖，同时胰岛中 SNAP25 表达和 ChREBP 磷酸化减少。SNAP25 的敲低降低了β细胞中的 GSIS，而 SNAP25 的过表达增加了β细胞中的 GSIS。ChREBP 的激活或过表达导致 SNAP25 表达减少，随后抑制 GSIS。相反，高葡萄糖引起的 SNAP25 表达减少被 ChREBP 敲低所缓解。从机制上讲，高葡萄糖激活 ChREBP 增加了其占有率，并降低了 Snap25 启动子上 H3K4me3 的水平。我们的研究结果揭示了 SNAP25 在β细胞中表达的新的调节机制，并表明 SNAP25 可能参与 ChREBP 控制的β细胞分泌功能的调节。
