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Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation

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

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Abstract

Excessive alcohol consumption is a major cause of acute pancreatitis, but the mechanism involved is not well understood. Recent investigations suggest that pancreatic ductal epithelial cells (PDECs) help defend the pancreas from noxious agents such as alcohol. Because the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel plays a major role in PDEC physiology and mutated CFTR is often associated with pancreatitis, we tested the hypothesis that ethanol affects CFTR to impair ductal function. Electrophysiological studies on native PDECs showed that ethanol (10 and 100 mM) increased basal, but reversibly blocked, forskolin-stimulated CFTR currents. The inhibitory effect of ethanol was mimicked by its non-oxidative metabolites, palmitoleic acid ethyl ester (POAEE) and palmitoleic acid (POA), but not by the oxidative metabolite, acetaldehyde. Ethanol, POAEE and POA markedly reduced intracellular ATP (ATP(i)) which was linked to CFTR inhibition since the inhibitory effects were almost completely abolished if ATP(i) depletion was prevented. We propose that ethanol causes functional damage of CFTR through an ATP(i)-dependent mechanism, which compromises ductal fluid secretion and likely contributes to the pathogenesis of acute pancreatitis. We suggest that the maintenance of ATP(i) may represent a therapeutic option in the treatment of the disease.


Publication metadata

Author(s): Judak L, Hegyi P, Rakonczay Z, Maleth J, Gray MA, Venglovecz V

Publication type: Article

Publication status: Published

Journal: Pflügers Archiv - European Journal of Physiology

Year: 2014

Volume: 466

Issue: 3

Pages: 549-562

Print publication date: 01/03/2014

ISSN (print): 0031-6768

ISSN (electronic): 1432-2013

Publisher: Springer

URL: http://dx.doi.org/10.1007/s00424-013-1333-x

DOI: 10.1007/s00424-013-1333-x


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Funding

Funder referenceFunder name
European Pancreatic Club fellowship
BO/00531/11/5Hungarian Academy of Sciences
BO 00174/10/5Hungarian Academy of Sciences
K109756Hungarian Scientific Research Fund
NF100677Hungarian Scientific Research Fund
OTKA NF105758Hungarian Scientific Research Fund
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
TAMOP-4.2.2.A-11/1/KONV-2012-0073Hungarian National Development Agency

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