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The Role of the Energy-Sensing AMP-Activated Protein Kinase in Intestinal Epithelial Physiology and Pathophysiology

  • Author(s): King, Stephanie
  • Advisor(s): McCole, Declan F
  • et al.
No data is associated with this publication.
Creative Commons 'BY-SA' version 4.0 license
Abstract

AMP-Activated Protein Kinase (AMPK) is a cellular energy sensor that regulates metabolic processes. The downstream effects of AMPK activation differ by type of stimulation, cell type or tissue, and state of the microenvironment. Various groups have suggested AMPK plays a protective role in the intestinal epithelium during both homeostasis and inflammation, however these studies have overlooked the need for increased specificity in order to definitively determine the effects of AMPK. In this study, I used \textit{in vitro} and tissue-specific \textit{in vivo} model systems to test the impact of AMPK activity at baseline and in different models of inflammation. I observed changes in intestinal permeability, protein and gene expression, transporter responses, and inflammatory signaling using molecular and physiological methodologies. I confirmed that AMPK does regulate intestinal barrier function during homeostasis, but that loss of these actions does not confer increased susceptibility to experimental colitis or pathogenic enteric infection. I confirmed AMPK promotes barrier function through expression of Claudin-4, acts as an inhibitor of calcium-dependent electrogenic ion transport, and represses expression of the basolateral cotransporter NKCC1. In addition, the regulatory effects of AMPK are maintained during oxidative stress where calcium-dependent electrogenic ion transport is suppressed due to AMPK-dependent phosphorylation and decreased activity of NKCC1. Loss of epithelial AMPK\textalpha{} resulted in decreased cell death during experimental colitis, however this did not ultimately impact course and severity of the disease. Finally, epithelial AMPK\textalpha{}-deficiency did not render mice more sensitive to infection with the murine enteric pathogen \textit{Citrobacter rodentium}. These data suggest AMPK plays a minor role in maintenance of the intestinal epithelium and that its association with protection in models of colitis could in part be due to other signaling molecules or AMPK activity in other cell types. Further work to more specifically modulate AMPK activity in the intestinal epithelium is needed to confirm if AMPK is anti- or pro-inflammatory in various contexts.

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This item is under embargo until January 27, 2022.