Basic—Liver, Pancreas, and Biliary TractAdaptive Unfolded Protein Response Attenuates Alcohol-Induced Pancreatic Damage
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Animals and Ethanol Feeding
Xbp1+/− and wild-type (Xbp1+/+, BALB/c) littermate mice were obtained by breeding Xbp1+/− mice generously provided by L. Glimcher. The phenotype of these mice is described elsewhere26 and in Supplementary Materials and Methods. For initial studies, we also used Wistar rats (Charles River, MA). Both rats and mice were fed control and ethanol-containing diets using the Tsukamoto–French intragastric ethanol infusion model.29 Animals were placed on diets for 6 (rats) or 4 (mice) weeks. Pancreatic
Ethanol Feeding Induced Activation of UPR and XBP1 in Rat Pancreas
As reported previously,5, 6 rats fed ethanol diets for 6 weeks using the Tsukamoto–French intragastric infusion model did not exhibit evidence of pancreatitis or acinar cell damage in H&E-stained tissue sections. Levels of blood lipase and intrapancreatic trypsin activity were similar in ethanol-fed and control-fed rats (not shown). However, electron microscopy analysis revealed structural changes, the most prominent being an extensive distention in the ER of acinar cells (Figure 1A). By
Discussion
Our results show that alcohol feeding in rodents induces UPR activation in pancreas, as indicated by increased expression of IRE1 and sXBP1. The results further show that when sXBP1 levels are diminished, as in Xbp1+/− mice, ethanol feeding induces ER stress and pancreas pathology. Based on these findings, we conclude that an adaptive UPR involving IRE1/XBP1 protects against alcohol-induced pathology in the exocrine pancreas.
Oxidative stress is a likely factor causing pancreatic ER stress in
Acknowledgment
The authors thank L. Glimcher and A. H. Lee for providing founder breeding pairs of Xbp1+/− mice, the Department of Veterans Affairs and the Animal and Morphology Cores of the Research Center for ALPD & Cirrhosis (P50-A11999) for their assistance with intragastric ethanol feeding and morphologic analyses of pancreatic tissues, and R. Waldron for his contribution to manuscript revision.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the National Institute on Alcohol Abuse and Alcoholism (grant R21 AA016010) and the National Center for Complementary and Alternative Medicine (grant 1P01AT003960).