November 12, 2014
Notes: Huang, Wei
Javed, Muhammad A
Halloran, Christopher M
Research Support, Non-U.S. Gov’t
World J Gastroenterol. 2013 Jul 28;19(28):4607-15. doi: 10.3748/wjg.v19.i28.4607.
Author Address: Sichuan Provincial Pancreatitis Center, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
Reference Type: Journal Article
Record Number: 4845Author: Huang, W., Booth, D. M., Cane, M. C., Chvanov, M., Javed, M. A., Elliott, V. L., Armstrong, J. A., Dingsdale, H., Cash, N., Li, Y., Greenhalf, W., Mukherjee, R., Kaphalia, B. S., Jaffar, M., Petersen, O. H., Tepikin, A. V., Sutton, R. and Criddle, D. N.
Title: Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis
Short Title: Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis
Alternate Journal: Gut
ISSN: 1468-3288 (Electronic)
Accession Number: 24162590
Keywords: Acinar Cells/drug effects/metabolism
Acyltransferases/*antagonists & inhibitors
Carboxylesterase/antagonists & inhibitors/*metabolism
Disease Models, Animal
Fatty Acids, Monounsaturated/pharmacology
Membrane Potential, Mitochondrial/*drug effects
Pancreatitis, Alcoholic/chemically induced/*metabolism/pathology
Abstract: OBJECTIVE: Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. DESIGN: Intracellular calcium ([Ca(2+)](C)), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. RESULTS: Inhibition of OME with 4-MP converted predominantly transient [Ca(2+)](C) rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. CONCLUSIONS: A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation.