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Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

Lookup NU author(s): Dr Zoltan Rakonczay, Viktoria Venglovecz, Dr Michael Gray


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BACKGROUND & AIMS: Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. METHODS: We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3-, levels and function of CFTR, and exchange of Cl- for HCO3- in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. RESULTS: Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3-, as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3',5'-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. CONCLUSIONS: Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis.

Publication metadata

Author(s): Maleth J, Balazs A, Pallagi P, Balla Z, Kui B, Katona M, Judak L, Nemeth I, Kemeny LV, Rakonczay Z, Venglovecz V, Foldesi I, Peto Z, Somoracz A, Borka K, Perdomo D, Lukacs GL, Gray MA, Monterisi S, Zaccolo M, Sendler M, Mayerle J, Kuhn JP, Lerch MM, Sahin-Toth M, Hegyi P

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2015

Volume: 148

Issue: 2

Pages: 427-439.e16

Print publication date: 01/02/2015

Online publication date: 07/11/2014

Acceptance date: 04/11/2014

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: W.B. Saunders Co.


DOI: 10.1053/j.gastro.2014.11.002


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Funder referenceFunder name
Alfried Krupp von Bohlen und Halbach Foundation (Graduate Schools of Tumour Biology and Free Radical Biology)
European Union
01ZZ0403Federal Ministry of Education and Research
03ZIK012Federal Ministry of Education and Research
01ZZ0103Federal Ministry of Education and Research
01ZZ9603Federal Ministry of Education and Research
109102Deutsche Krebshilfe/Dr Mildred Scheel Stiftung
BMBF GANI-MED 03152061AFederal Ministry of Education and Research
DFG GRK1947Deutsche Forschungsgemeinschaft
DFG GRK840-E3/E4Deutsche Forschungsgemeinschaft
BMBF 0314107Federal Ministry of Education and Research
LP2014-10/2014MTA-SZTE Momentum Grant
MA 4115/1-2/3Deutsche Forschungsgemeinschaft
NF100677Hungarian Scientific Research Fund
R01 DK058088National Institutes of Health (NIH)
TAMOP-4.2.2.A-11/1/KONV-2012-0073Hungarian National Development Agency
TAMOP-4.2.4.A2-SZJO-TOK-13-0017Hungarian National Development Agency
TAMOP-4.2.2.A-11/1/KONV-2012-0035Hungarian National Development Agency
TAMOP-4.2.2-A-11/1/KONV-2012-0052Hungarian National Development Agency
TAMOP-4.2.4.A/2-11-1-2012-0001Hungarian National Development Agency