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

  • Molecular and cellular mechanisms of disease
  • Published:
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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 (ATPi) which was linked to CFTR inhibition since the inhibitory effects were almost completely abolished if ATPi depletion was prevented. We propose that ethanol causes functional damage of CFTR through an ATPi-dependent mechanism, which compromises ductal fluid secretion and likely contributes to the pathogenesis of acute pancreatitis. We suggest that the maintenance of ATPi may represent a therapeutic option in the treatment of the disease.

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Abbreviations

Ac:

Acetaldehyde

AP:

Acute pancreatitis

ATPi :

Intracellular ATP

BNPP:

bis-(4-Nitrophenyl) phosphate

CCCP:

Carbonyl cyanide m-chlorophenyl hydrazone

CFTR:

Cystic fibrosis transmembrane conductance regulator

DMSO:

Dimethyl sulphoxide

DOG:

2-Deoxyglucose

IAA:

Iodoacetamide

EGTA:

Ethylene glycol tetraacetic acid

FA:

Fatty acid

FAEE:

Fatty acid ethyl ester

MgGreen-AM:

Magnesium Green-AM

PDECs:

Pancreatic ductal epithelial cells

POA:

Palmitoleic acid

POAEE:

Palmitoleic acid ethyl ester

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Acknowledgments

Our research is supported by Hungarian National Development Agency grants (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), the Hungarian Scientific Research Fund (OTKA NF105758, NF100677, K109756), the Hungarian Academy of Sciences (BO 00174/10/5 and BO/00531/11/5), and a European Pancreatic Club fellowship to Linda Judák.

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The authors hereby declare that there is no conflict of interest to disclose.

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Judák, L., Hegyi, P., Rakonczay, Z. et al. Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation. Pflugers Arch - Eur J Physiol 466, 549–562 (2014). https://doi.org/10.1007/s00424-013-1333-x

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