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Waldron RT, Su HY, Piplani H, et al. Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model. Cell Mol Gastroenterol Hepatol. 2018;5(4):479-497doi: 10.1016/j.jcmgh.2018.01.001.
Waldron, R. T., Su, H. Y., Piplani, H., Capri, J., Cohn, W., Whitelegge, J. P., Faull, K. F., Sakkiah, S., Abrol, R., Yang, W., Zhou, B., Freeman, M. R., Pandol, S. J., & Lugea, A. (2018). Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model. Cellular and molecular gastroenterology and hepatology, 5(4), 479-497. https://doi.org/10.1016/j.jcmgh.2018.01.001
Waldron, Richard T, et al. "Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model." Cellular and molecular gastroenterology and hepatology vol. 5,4 (2018): 479-497. doi: https://doi.org/10.1016/j.jcmgh.2018.01.001
Waldron RT, Su HY, Piplani H, Capri J, Cohn W, Whitelegge JP, Faull KF, Sakkiah S, Abrol R, Yang W, Zhou B, Freeman MR, Pandol SJ, Lugea A. Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model. Cell Mol Gastroenterol Hepatol. 2018 Jan 06;5(4):479-497. doi: 10.1016/j.jcmgh.2018.01.001. eCollection 2018. PMID: 29930975; PMCID: PMC6009017.
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Cell Mol Gastroenterol Hepatol. 2018 Jan 06;5(4):479-497. doi: 10.1016/j.jcmgh.2018.01.001. eCollection 2018.

Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model.

Cellular and molecular gastroenterology and hepatology

Richard T Waldron, Hsin-Yuan Su, Honit Piplani, Joseph Capri, Whitaker Cohn, Julian P Whitelegge, Kym F Faull, Sugunadevi Sakkiah, Ravinder Abrol, Wei Yang, Bo Zhou, Michael R Freeman, Stephen J Pandol, Aurelia Lugea

Affiliations

  1. Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
  2. Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California.
  3. Psychiatry and Biobehavioral Sciences, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California.

PMID: 29930975 PMCID: PMC6009017 DOI: 10.1016/j.jcmgh.2018.01.001

Abstract

BACKGROUND & AIMS: Heavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk. Mice fed ethanol long term show no pancreas damage unless adaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ER proteins.

METHODS: Wild-type and

RESULTS: Ethanol feeding and

CONCLUSIONS: Results documented in ethanol-fed mice lacking sufficient spliced XBP1 illustrate consequences of ER stress extended by preventing unfolded protein response from fully restoring pancreatic acinar cell proteostasis during ethanol-induced redox challenge. In this model, orderly protein folding and transport to the secretory pathway were disrupted, and abundant molecules including Cel with perturbed structures were retained in ER, promoting ER stress-related pancreas pathology.

Keywords: %-ox, percentage oxidized; ATPase, adenosine triphosphatase; Alcohol Pancreatitis; Carboxyl Ester Lipase; Cel, carboxyl ester lipase; DTT, dithiothreitol; Disulfide Bond; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum–associated degradation; FAEE, fatty acid ethyl esters; FP, fluorophosphonate; ICAT, isotope-coded affinity tags; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MW, molecular weight; RER, rough ER; UPR, unfolded protein response; Unfolded Protein Response; WT, wild type; sXBP1, spliced X box-binding protein 1

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