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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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 (OGTPanc+/−) 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 OGTPanc+/− mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-α in OGTPanc+/− 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.

Details

Title
Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model
Author
Moore, Mackenzie 1   VIAFID ORCID Logo  ; Avula, Nandini 2   VIAFID ORCID Logo  ; Wong, Alicia 3 ; Beetch, Megan 2 ; Seokwon Jo 2 ; Alejandro, Emilyn U 2   VIAFID ORCID Logo 

 Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; [email protected] (M.M.); [email protected] (N.A.); [email protected] (M.B.); [email protected] (S.J.); Department of Surgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA 
 Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; [email protected] (M.M.); [email protected] (N.A.); [email protected] (M.B.); [email protected] (S.J.) 
 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 
First page
347
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20797737
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2642340411
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.