Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model

SIMPLE SUMMARY: Acute pancreatitis (AP) is a common disease with significant co-morbidity and increasing global incidence over the past 40 years. Current understanding of molecular underpinnings that facilitates one’s susceptibility to this inflammatory disease is less understood. The protein O-GlcNAc Transferase (OGT) is a cytosolic/nuclear/mitochondrial post-translational glycosylation enzyme that is highly expressed in the pancreas. Here, we propose that OGT, which has been associated with regulating many inflammatory responses such as NFκB signaling, provides the mechanistic link to AP induction and susceptibility. In this study, a mouse model with pancreatic OGT loss was generated and subjected to cerulein, a common pancreatitis inducer. Pancreas OGT-deficient mice exhibited reduced severity of AP, associated with reduced inflammatory markers as well as decreased macrophage population in the pancreas. In conclusion, these data indicate that OGT is a molecular driver that facilitates cerulein-induced AP in vivo. ABSTRACT: Acute pancreatitis (AP) involves premature trypsinogen activation, which mediates a cascade of pro-inflammatory signaling that causes early stages of pancreatic injury. Activation of the transcription factor κB (NF-κB) and secretion of pro-inflammatory mediators are major events in AP. O-GlcNAc transferase (OGT), a stress-sensitive enzyme, was recently implicated to regulate NF-κB activation and inflammation in AP in vitro. This study aims to determine whether a pancreas-specific transgenic reduction in OGT in a mouse model affects the severity of AP in vivo. Mice with reduced pancreatic OGT (OGT(Panc+/−)) at 8 weeks of age were randomized to cerulein, which induces pancreatitis, or saline injections. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGT(Panc+/−) mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-α in OGT(Panc+/−) did not significantly increase in response to cerulein treatment as compared to controls, suggesting attenuated AP induction in this model. Our study reveals the effect of reducing pancreatic OGT levels on the severity of pancreatitis, warranting further investigation on the role of OGT in the pathology of AP.