Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage

Gastroenterology. 2011 Mar;140(3):987-97. doi: 10.1053/j.gastro.2010.11.038. Epub 2010 Nov 25.

Abstract

Background & aims: Endoplasmic reticulum (ER) stress responses (collectively known the unfolded protein response [UPR]) have important roles in several human disorders, but their contribution to alcoholic pancreatitis is not known. We investigated the role of X-box binding protein 1 (XBP1), a UPR regulator, in prevention of alcohol-induced ER stress in the exocrine pancreas.

Methods: Wild-type and Xbp1(+/-) mice were fed control or ethanol diets for 4 weeks. Pancreatic tissue samples were then examined by light and electron microscopy to determine pancreatic alterations; UPR regulators were analyzed biochemically.

Results: In wild-type mice, ethanol activated a UPR, increasing pancreatic levels of XBP1 and XBP1 targets such as protein disulfide isomerase (PDI). In these mice, pancreatic damage was minor. In ethanol-fed Xbp1(+/-) mice, XBP1 and PDI levels were significantly lower than in ethanol-fed wild-type mice. The combination of XBP1 deficiency and ethanol feeding reduced expression of regulators of ER function and the up-regulation of proapoptotic signals. Moreover, ethanol feeding induced oxidation of PDI, which might compromise PDI-mediated disulfide bond formation during ER protein folding. In ethanol-fed Xbp1(+/-) mice, ER stress was associated with disorganized and dilated ER, loss of zymogen granules, accumulation of autophagic vacuoles, and increased acinar cell death.

Conclusions: Long-term ethanol feeding causes oxidative ER stress, which activates a UPR and increases XBP1 levels and activity. A defective UPR due to XBP1 deficiency results in ER dysfunction and acinar cell pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Ethanol
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pancreas, Exocrine / metabolism*
  • Pancreas, Exocrine / pathology
  • Pancreatitis, Alcoholic / genetics
  • Pancreatitis, Alcoholic / metabolism*
  • Pancreatitis, Alcoholic / pathology
  • Pancreatitis, Alcoholic / prevention & control
  • Protein Disulfide-Isomerases / metabolism
  • Rats
  • Rats, Wistar
  • Regulatory Factor X Transcription Factors
  • Stress, Physiological*
  • Tissue Culture Techniques
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Unfolded Protein Response*
  • X-Box Binding Protein 1

Substances

  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Xbp1 protein, rat
  • Ethanol
  • Protein Disulfide-Isomerases