Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis

József Maléth, Anita Balázs, Petra Pallagi, Zsolt Balla, Balázs Kui, Máté Katona, Linda Judák, István Németh, Lajos V. Kemény, Zoltán Rakonczay, Viktória Venglovecz, Imre Földesi, Zoltán Peto, Áron Somorácz, Katalin Borka, Doranda Perdomo, Gergely L. Lukacs, Mike A. Gray, Stefania Monterisi, Manuela Zaccolo & 6 others Matthias Sendler, Julia Mayerle, Jens Peter Kühn, Markus M. Lerch, Miklós Sahin-Tóth, Péter Hegyi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)427-439
Number of pages13
JournalGastroenterology
Volume148
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

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Cystic Fibrosis Transmembrane Conductance Regulator
Pancreatitis
Alcohols
Ethanol
Fatty Acids
Chronic Pancreatitis
Fluids and Secretions
Healthy Volunteers
Guinea Pigs
Sweat
Knockout Mice
Chlorides
Cell Line
RNA Stability
Mitochondrial Membranes
Cystic Fibrosis
Alcohol Drinking
Endoplasmic Reticulum
Cyclic AMP

Keywords

  • Alcoholism
  • Cl Channel
  • Duct
  • Exocrine Pancreas

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. / Maléth, József; Balázs, Anita; Pallagi, Petra; Balla, Zsolt; Kui, Balázs; Katona, Máté; Judák, Linda; Németh, István; Kemény, Lajos V.; Rakonczay, Zoltán; Venglovecz, Viktória; Földesi, Imre; Peto, Zoltán; Somorácz, Áron; Borka, Katalin; Perdomo, Doranda; Lukacs, Gergely L.; Gray, Mike A.; Monterisi, Stefania; Zaccolo, Manuela; Sendler, Matthias; Mayerle, Julia; Kühn, Jens Peter; Lerch, Markus M.; Sahin-Tóth, Miklós; Hegyi, Péter.

In: Gastroenterology, Vol. 148, No. 2, 01.02.2015, p. 427-439.

Research output: Contribution to journalArticle

Maléth, J, Balázs, A, Pallagi, P, Balla, Z, Kui, B, Katona, M, Judák, L, Németh, I, Kemény, LV, Rakonczay, Z, Venglovecz, V, Földesi, I, Peto, Z, Somorácz, Á, Borka, K, Perdomo, D, Lukacs, GL, Gray, MA, Monterisi, S, Zaccolo, M, Sendler, M, Mayerle, J, Kühn, JP, Lerch, MM, Sahin-Tóth, M & Hegyi, P 2015, 'Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis', Gastroenterology, vol. 148, no. 2, pp. 427-439. https://doi.org/10.1053/j.gastro.2014.11.002
Maléth, József ; Balázs, Anita ; Pallagi, Petra ; Balla, Zsolt ; Kui, Balázs ; Katona, Máté ; Judák, Linda ; Németh, István ; Kemény, Lajos V. ; Rakonczay, Zoltán ; Venglovecz, Viktória ; Földesi, Imre ; Peto, Zoltán ; Somorácz, Áron ; Borka, Katalin ; Perdomo, Doranda ; Lukacs, Gergely L. ; Gray, Mike A. ; Monterisi, Stefania ; Zaccolo, Manuela ; Sendler, Matthias ; Mayerle, Julia ; Kühn, Jens Peter ; Lerch, Markus M. ; Sahin-Tóth, Miklós ; Hegyi, Péter. / Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. In: Gastroenterology. 2015 ; Vol. 148, No. 2. pp. 427-439.
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T1 - Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis

AU - Maléth, József

AU - Balázs, Anita

AU - Pallagi, Petra

AU - Balla, Zsolt

AU - Kui, Balázs

AU - Katona, Máté

AU - Judák, Linda

AU - Németh, István

AU - Kemény, Lajos V.

AU - Rakonczay, Zoltán

AU - Venglovecz, Viktória

AU - Földesi, Imre

AU - Peto, Zoltán

AU - Somorácz, Áron

AU - Borka, Katalin

AU - Perdomo, Doranda

AU - Lukacs, Gergely L.

AU - Gray, Mike A.

AU - Monterisi, Stefania

AU - Zaccolo, Manuela

AU - Sendler, Matthias

AU - Mayerle, Julia

AU - Kühn, Jens Peter

AU - Lerch, Markus M.

AU - Sahin-Tóth, Miklós

AU - Hegyi, Péter

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

KW - Alcoholism

KW - Cl Channel

KW - Duct

KW - Exocrine Pancreas

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