Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis


Huang, Wei, Booth, David, Cane, MC, Chvanov, Michael, Javed, MA, Elliott, Vicki, Armstrong, Jane, Dingsdale, H, Cash, Nicole, Yan, Li et al (show 8 more authors) (2014) Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis. Gut, 63 (8). pp. 1313-1324.

[img] Text
Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis.pdf - Unspecified
Available under License Creative Commons Attribution.
Download (21MB)

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 ([Ca2+]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 [Ca2+]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.

Item Type: Article
Additional Information: Huang, Wei Booth, David M Cane, Matthew C Chvanov, Michael Javed, Muhammad A Elliott, Victoria L Armstrong, Jane A Dingsdale, Hayley Cash, Nicole Li, Yan Greenhalf, William Mukherjee, Rajarshi Kaphalia, Bhupendra S Jaffar, Mohammed Petersen, Ole H Tepikin, Alexei V Sutton, Robert Criddle, David N G0700167/Medical Research Council/United Kingdom G19/22/Medical Research Council/United Kingdom KO12967/Medical Research Council/United Kingdom MR/J002771/1/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England Gut Gut. 2014 Aug;63(8):1313-24. doi: 10.1136/gutjnl-2012-304058. Epub 2013 Oct 25.## TULIP Type: Articles/Papers (Journal) ##
Uncontrolled Keywords: Cells, Cultured, Mitochondria, Animals, Mice, Pancreatitis, Alcoholic, Disease Models, Animal, Necrosis, Calcium, Ethanol, Pyrones, Pyrazoles, NADP, Carboxylesterase, Acyltransferases, Fatty Acids, Fatty Acids, Monounsaturated, Apoptosis, Calcium Signaling, Membrane Potential, Mitochondrial, Acinar Cells, Fomepizole
Depositing User: Symplectic Admin
Date Deposited: 13 Nov 2015 10:54
Last Modified: 15 Dec 2022 08:03
DOI: 10.1136/gutjnl-2012-304058
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2036843
Dimensions
Altmetric
CORE (COnnecting REpositories)