166-OR: The Alpha–Catenin–Cholesterol Biosynthesis Axis Regulates Tight Junction Formation in Pancreatic Islets

Introduction & Objective: The functionality of pancreatic islets relies on the structural integrity of cellular junctions, such as tight junctions (TJs). At the heart of this junctional integrity is the cell adhesion protein Alpha-Catenin (Ctnna1). Alterations in Ctnna1 result in impaired islet clustering and functionality. We observed that islet cells with targeted Ctnna1 ablation (Ctnna1-KO) showed weakened TJs and diminished cholesterol biosynthesis. Recognizing the vital relationship between TJs and cholesterol-rich domains for cellular integrity, we explored Ctnna1's role in modulating TJ formation through the cholesterol biosynthesis pathway. We aim to deepen our understanding of cellular cohesion mechanisms and identify potential therapeutic strategies to enhance pancreatic islet functionality.

Methods: We crossbred mice with Ngn3-promoter-driven Cre recombinase and Ctnna1^flox/flox. We analyzed pancreata across various developmental stages and conducted rescue experiments comparing TJ formation in control and Ctnna1-KO mice. This included treating isolated 8-week-old mouse islets with cholesterol or its intermediate precursors isoprenoids in vitro and feeding 8-week-old mice a high-fat diet for eight weeks in vivo. Complementary experiments with human islets treated with statin provided further human context.

Results: Our findings indicate a significant compromise in the structural integrity of TJs in the absence of alpha-Catenin. However, cholesterol supplementation partially restored this integrity, suggesting a potential pathway for therapeutic intervention.

Conclusions: Our study highlights the pivotal role of alpha-Catenin-dependent cholesterol biosynthesis in maintaining the structural and functional integrity of tight junctions within pancreatic islets. Manipulating this pathway could offer new avenues for therapeutic interventions to preserve or enhance islet function, potentially impacting diabetes treatment.