Caveolin-1 Modulates Islet Amyloid Polypeptide Expression Through Interaction with TXNIP in Murine Pancreatic β-Cells.

Background: Pathological aggregation of islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Our previous studies demonstrated that caveolin-1 (Cav-1) deficiency protects β-cells from palmitate-induced apoptosis. Microarray profiling further indicated that Cav-1 silencing alters IAPP expression. This study aimed to investigate the effects of Cav-1 depletion on IAPP secretion and expression and to explore the potential involvement of thioredoxin-interacting protein (TXNIP). Methods: We performed lentiviral-mediated Cav-1 knockdown in NIT-1 cells and isolated murine islets, and simultaneously generated an inducible β-cell-specific Cav-1 knockout (iβ-Cav1 KO) mouse model. IAPP secretion and expression were assessed by ELISA, Western blot, qPCR and immunofluorescence. The expression of IAPP-processing enzymes (PAM, PC1, and PC2) and degradation factors (IDE and BACE2) was examined. Co-immunoprecipitation (Co-IP) and immunofluorescence were performed to investigate the interaction between Cav-1 and TXNIP. Results: Cav-1 depletion significantly reduced both IAPP secretion and expression in vitro and in vivo. High-fat-diet-fed iβ-Cav1 KO mice exhibited the lowest serum IAPP levels. Mechanistically, Cav-1 depletion was associated with downregulation of PAM, PC1, and PC2 and upregulation of IDE and BACE2. Additionally, Cav-1 depletion decreased TXNIP expression. Immunofluorescence revealed co-localization of Cav-1 and TXNIP, and co-immunoprecipitation further demonstrated their direct physical interaction. Conclusions: Cav-1 is essential for IAPP secretion and expression in β-cells. The direct physical interaction between Cav-1 and TXNIP suggests that TXNIP may mediate the regulatory effects of Cav-1 on IAPP processing or secretion. These findings identify the Cav-1-TXNIP axis as a potential target for mitigating IAPP-related β-cell dysfunction.