Impaired FXR-Syntaxin 1A Pathway Contributes to Diabetic β-Cell Secretory Dysfunction.

Abstract

Impaired insulin secretion, a hallmark of type 2 diabetes (T2D), is associated with the downregulation of syntaxin 1A (encoded by Stx1a), a core SNARE protein essential for insulin exocytosis, in pancreatic β-cells. However, the mechanism regulating syntaxin 1A expression remains unclear. This study aimed to determine the role of the nuclear receptor farnesoid X receptor (FXR) in modulating syntaxin 1A expression. We demonstrated that syntaxin 1A expression was significantly reduced in islets from diabetic Goto-Kakizaki (GK) rats and in INS-1 832/13 cells exposed to chronic high glucose. FXR levels were similarly diminished under these diabetic conditions. Genetic knockdown or knockout of FXR in β-cells markedly decreased syntaxin 1A expression and impaired glucose-stimulated insulin secretion (GSIS). Conversely, activation of FXR with GW4064 or chenodeoxycholic acid (CDCA) robustly upregulated syntaxin 1A expression. Chromatin immunoprecipitation assays revealed that FXR activation enhanced its binding to a conserved response element in the Stx1a promoter, facilitating the recruitment of the coactivator steroid receptor coactivator-1 (SRC-1) and increasing histone H3 acetylation, an epigenetic marker for active transcription. Intriguingly, FXR also promoted its own expression through a positive autoregulatory loop. Collectively, these findings identify FXR as a key transcriptional regulator of syntaxin 1A in β-cells. The impairment of the FXR-syntaxin 1A pathway contributes to the secretory dysfunction of diabetic β-cells, revealing a novel pathogenic mechanism underlying T2D.