The Role of O-linked N-Acetylglucosamine Transferase in the Pathophysiology of Acute Pancreatitis

Abstract

Background: Acute pancreatitis (AP) involves the premature activation of trypsin which leads to a cascade of pro-inflammatory signaling, NFκB activation, and organelle dysfunction in the acinar cells which can lead to a severe systemic inflammatory response. O-GlcNAc transferase (OGT) is an enzyme that regulates multiple components of this cascade. The role of OGT has been studied in several inflammatory conditions where its effects appear to be specific to the physiological context. In vitro studies have demonstrated that reducing OGT decreases the severity of pancreatitis, but in vivo studies are lacking. This study aims to determine if a pancreas-specific transgenic reduction of OGT in a mouse model affects the severity of AP. Methods: Mice with reduced pancreatic OGT (OGTPanc+/-) were generated utilizing the Cre-Lox system. At 8 weeks of age, mice were randomized to cerulein, which induces pancreatitis, or saline injections. The severity of pancreatitis was scored based on histology. Serum levels of IL-1β, IL-6, and TNF-α were obtained as well as amylase, lipase, and LDH. NFκB activity and inflammatory markers were evaluated in pancreatic tissue. Results: Mice with reduced pancreatic OGT had similar body weight, blood glucose, and glucose homeostasis as controls. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGTPanc+/- mice had a decreased severity of AP. In addition, lipase, LDH, and TNF-α did not increase in response to cerulein treatment as compared to controls. Conclusions: In this mouse model, a reduction of pancreatic OGT attenuates the severity of acute pancreatitis which is consistent with previous in vitro studies but changes to the NFκB pathway were not identified. Future studies are needed to explore additional mechanisms to explain the effect of reducing pancreatic OGT on the severity of pancreatitis and to investigate the inhibition of OGT as a potential therapeutic approach.