Background & Objective:Lipotoxicity exacerbates β-cell injury to contribute type 2 diabetes development. In lipotoxic conditions, secretagogin (SCGN), a protein highly expressed in islets, is found to undergo downregulation. Thus, we aim to explore the role of SCGN in lipotoxicity-induced β-cell injury.
Methods: MIN6 cells were exposed to ox-LDL to simulate lipotoxic damage. To modulate SCGN expression, the pcDNA3.1-Scgn vector or SCGN-specific siRNAs were utilized in MIN6 cells. To reinstate SCGN expression, we administered AAV-9 carrying SCGN in high-fat diets (HFD) mice. Cell viability was evaluated through MTT and PI assays, pyroptotic pathway was assessed using PCR, western blotting, and immunofluorescence techniques.
Results: Exposure to ox-LDL in vitro or an HFD in vivo decreases SCGN expression and actives pyroptosis. Restoring SCGN expression partially reverses this effect. The mechanism behind this involves the downregulation of SCGN facilitates ChREBP translocation from cytosol to the nucleus. This, ultimately, promotes TXNIP transcription, activating the NLRP3/Caspase-1 pathway.
Conclusion: Lipotoxicity-induced SCGN downregulation facilitates ChREBP translocation from the cytosol to nucleus. This, subsequently, triggers
TXNIP transcription, leading to the activation of NLRP3/caspase-1 pyroptotic pathway. Ultimately, resulting in pyroptotic pancreatic β-cells death.
J. Yang: None. S. Ouyang: None. S. xiang: None.
National Natural Science Foundation of China (82170852)
