Gastroenterology

Gastroenterology

Volume 148, Issue 2, February 2015, Pages 427-439.e16
Gastroenterology

Original Research
Full Report: Basic and Translational—Pancreas
Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

https://doi.org/10.1053/j.gastro.2014.11.002Get rights and content
Under a Creative Commons license
open access

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.

Keywords

Exocrine Pancreas
Cl Channel
Alcoholism
Duct

Abbreviations used in this paper

AP
acute pancreatitis
ATP
adenosine triphosphate
ATPase
adenosine triphosphatase
(ATP)i
intracellular adenosine triphosphate
BAC
blood alcohol concentration
[Ca2+]i
intracellular Ca2+ concentration
cAMP
adenosine 3′,5′-cyclic monophosphate
CF
cystic fibrosis
CFTR
cystic fibrosis transmembrane conductance regulator
Clsw
sweat Cl concentration
CP
chronic pancreatitis
ER
endoplasmic reticulum
H2DIDS
dihydro-4,4′-diisothiocyanostilbene-2,2′-disulfonic acid
IP3R
inositol triphosphate receptor
KO
knockout
mRNA
messenger RNA
PDEC
pancreatic ductal epithelial cell
PA
palmitic acid
POA
palmitoleic acid
POAEE
palmitoleic acid ethyl ester
Tg
thapsigargin
WT
wild-type

Cited by (0)

Conflicts of interest The authors disclose no conflicts.

Funding Supported by MTA-SZTE Momentum Grant (LP2014-10/2014), by the Hungarian National Development Agency (TÁMOP-4.2.2.A-11/1/KONV-2012-0035, TÁMOP-4.2.2-A-11/1/KONV-2012-0052, TÁMOP-4.2.2.A-11/1/KONV-2012-0073, TÁMOP-4.2.4.A/2-11-1-2012-0001, TÁMOP-4.2.4.A2-SZJÖ-TOK-13-0017) and the Hungarian Scientific Research Fund (NF100677). M.M.L. was supported by grants from the Alfried Krupp von Bohlen und Halbach Foundation (Graduate Schools of Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/Dr Mildred Scheel Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, DFG GRK1947, MA 4115/1-2/3), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012), and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1, EPC-TM-Net). MS-T was supported by the National Institutes of Health (NIH) grant R01 DK058088.

Author names in bold designate shared co-first authorship.