Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage.
OBJECTIVE
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.
Southern California Research Center for ALPD & Cirrhosis, Veterans Administration Greater Los Angeles Healthcare System/University of California, Los Angeles, California 90073, USA. alugea@ucla.edu
Aurelia
A
Lugea
David
D
Tischler
Janie
J
Nguyen
Jun
J
Gong
Ilya
I
Gukovsky
Samuel W
SW
French
Fred S
FS
Gorelick
Stephen J
SJ
Pandol
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D000431:Ethanol; D019704:Protein Disulfide-Isomerases