The pathogenesis of alcoholic liver disease involves elevated plasma endotoxin and endotoxin mediated liver injury. Evidence from clinical and experimental studies suggests that elevated endotoxin level in alcoholism involves overgrowth of endotoxin producing bacteria and increased intestinal absorption of endotoxin. The investigators recently demonstrated that acetaldehyde the oxidative product of ethanol, known to be generated in the intestine, increases paracellular permeability in Caco-2 cell monolayers, an intestinal epithelial model. The acetaldehyde increase in permeability is mediated by a tyrosine kinase dependent mechanism and is associated with an inhibition of protein tyrosine phosphatase (PTPase) and increased protein tyrosine phosphorylation. The acetaldehyde effects on permeability was inhibited by L-glutamine, an amino acid considered for its therapeutic benefits in various gastrointestinal disorders. On the basis of preliminary results it is hypothesized that: 1) acetaldehyde dissociates protein complexes at the epithelial junctions by inducing tyrosine phosphorylation of b-catenin by regulating PTP1B (a PTPase), and 2) L-glutamine prevents acetaldehyde-induced increase in permeability by blocking the ability of acetaldehyde to inhibit PTP1B and increased tyrosine phosphorylation of b-catenin. Using the above mentioned model of intestinal epithelia, the investigators propose to determine: a) If acetaldehyde induces a dissociation of occludin/Z0-1 and E-Cadherin/b-catenin complexes. b) Whether acetaldehyde induces phosphorylation of b-catenin and specific tyrosine residues. c) Whether acetaldehyde inhibits PTP1B. d) If over expression of PTP1B delays acetaldehyde induced permeability and expression of phosphatase inactive PTP1B mutants decreases permeability, and e) If L-glutamine prevents acetaldehyde inhibition of PTP1B tyrosine phosphorylation of b-catenin and dissociation of E-cadherin/b-catenin complex. The information derived from these studies has the potential to expand our understanding of alcohol mediated increase in endotoxin absorption by identifying some of the mechanisms of acetaldehyde induced disruption of paracellular junctions and protection by L-glutamine.
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