Dissociation of E-cadherin and beta-catenin in a mouse model of total parenteral nutrition: a mechanism for the loss of epithelial cell proliferation and villus atrophy.

Total parenteral nutrition (TPN) leads a loss of epithelial barrier function, decline in epithelial cell (EC) proliferation, and decreased expression of E-cadherin. As a large portion of intracellular beta-catenin is tightly associated with E-cadherin, we hypothesized that the loss of E-cadherin would result in a redistribution of intracellular beta-catenin, and could be a contributing mechanism for this TPN-associated loss of EC proliferation. An assessment of small bowel epithelium was performed in mice given either enteral nutrition (Control) or intravenous nutrition (TPN). TPN significantly down-regulated E-cadherin and beta-catenin expression, and resulted in a loss of a colocalization of these factors. TPN also up-regulated phosphorylated (p)-beta-catenin (Ser31/33,Thr41) and down-regulated (p)-beta-catenin(Ser552) expression. To further address mechanisms driving this, we observed a significant decrease in the abundance of p-AKT and p-GSK3beta expression, and an associated decline in tcf-4 transcription factors (cyclin D1, c-myc and Axin2), as well as a loss of EC proliferation by 7 days. To address whether the mechanism driving these changes was the absence of nutritional factors, glutamine was added to the TPN solution. This resulted in a partial restoration of beta-catenin expression and EC proliferation, suggesting that an alteration in nutrient delivery may affect many of these changes. Based on these findings, the loss of EC proliferation with TPN may well be due to a loss of total beta-catenin, as well as a concomitant change in the differential expression of beta-catenin phosphorylation sites, and a reduction in beta-catenin mediated tcf-4 transcription. This potential pathway may well explain many of the findings of mucosal atrophy associated with TPN.